Caspase inhibitors and methods of use thereof

ABSTRACT

Provided herein are compounds of formula I, compositions comprising the compounds and method of treating various diseases with the compounds and compositions.

1. RELATED APPLICATIONS

This application claims the benefit of the priority of U.S. ProvisionalApplication No. 62/815,270, filed Mar. 7, 2019, the disclosure of whichis incorporated herein by reference in its entirety.

2. FIELD

Provided herein are compounds that are caspase inhibitors,pharmaceutical compositions containing these compounds and methods ofusing such compounds and pharmaceutical compositions.

3. BACKGROUND

There are twelve known human caspases. Caspase-1, also known asinterleukin converting enzyme (ICE), was the first identified humancaspase. Ten caspases have been classified in two groups, based on theireffects: proapoptotic caspases (caspases 2, 3, 6, 7, 8, 9 and 10) orproinflammatory caspases (caspases 1, 4 and 5). The function of twoadditional human caspases (12 and 14) are less well characterized

Caspases are a family of cysteine protease enzymes that are keymediators in the signaling pathways for apoptosis and cell disassembly(Thornberry, Chem. Biol., 1998, 5, R97-R103). These signaling pathwaysvary depending on cell type and stimulus, but all apoptosis pathwaysappear to converge at a common effector pathway leading to proteolysisof key proteins. Caspases are involved in both the effector phase of thesignaling pathway and further upstream at its initiation. The upstreamcaspases involved in initiation events become activated and in turnactivate other caspases that are involved in the later phases ofapoptosis.

The substrate specificity of human ICE has been defined with the use ofpeptides that span the cleavage site of the enzyme. Two features ofpeptide substrates are essential for catalytic recognition by theenzyme. First, there is a strong preference for aspartic acid adjacentto the cleavage site, in that any substitution of this residue in theIL-1β precursor and peptide substrates leads to a substantial reductionin the rate of catalysis (Kostura, et al., Proc. Natl. Acad. Sci.,86:5227, 1989; Sleath, et al., J. Biol. Chem., 265:14526, 1990; Howard,et al., J. Immunol., 147:2964, 1991).

Enzymatically active caspase-1 is generated from its inactive precursor,pro-caspase-1, by the action of protein complexes known asinflammasomes. The biochemical function of inflammasomes is to is togenerate active caspase-1. Active caspase-1 converts the inactiveprecursor, pro-interleukin-1β (pro-interleukin-1β) to the activecytokine interleukin-1β (interleukin-1β), as well as pro-IL-18 tomature, active interleukin-1β. IL-1β is known as a masterproinflammatory cytokine and is involved in multiple human diseases.IL-18 is also a proinflammatory cytokine associated with human disease.Caspase-1 also cleaves the protein gasdermin D which initiates a form ofinflammatory cell death known as pyroptosis. Sollberger, G. et al.,Innate Immunity 20, pp. 115-125 (2013) and Denes, A et al. Cell DeathDisease 3, e338 (2012). Caspase-1 is implicated in numerous inflammatorydisease conditions due to its role in regulating the production ofproinflammatory cytokines and activating pyroptosis. Caspase-1 and IL-1βhave been linked with autoinflammatory diseases, autoimmune diseases,CNS diseases, liver diseases, respiratory diseases, cardiovasculardiseases, dermatological diseases, rheumatological diseases, kidneydiseases, ophthalmological diseases and cancers. Flores, J. et al.,Nature Comm. 9, 3916 (2018); McKenzie, B. et al., PNAS 115, (26),E6065-E6074 (2018); Melnikov, V. et al., J Clin Invest. 110, pp.1083-1091 (2002); Wang, W. et al., PNAS, 113, (34) pp. 9587-9592 (2016);Morrison, M. et al., Int J Obesity Res. 40, pp. 1416-1423 (2016); Guo B.et al., Sci Rep. 6, p. 36107 (2016); Stack, J. et al., J. Immunol. 175,pp. 2630-2634 (2005); Kim, R. et al., Am. J. Resp. Care Med. 196, pp.283-297 (2017); Rudolphi, K. et al., Osteoarthritis Cartilage 11, pp.738-746 (2003); Audia, J. et al., Basic Res. Cardiol. 113, (5), pp. 32(2018); Aira, L. et al., J. Invest. Derm. DOI: 10.1016/j.jid.2018.11.031(2018), Wooff, Y. et al., Sci. Rep. 10, p. 2263 (2020). Therefore,inhibitors of the proinflammatory and pathogenic actions of caspase-1,caspase-4 and caspase-5 could be beneficial in the treatment of multiplehuman diseases.

In view of the multiple uses for caspase inhibitors, there is a constantneed to develop new, more effective compounds that can selectivelyinhibit certain caspases.

4. SUMMARY

Provided herein are compounds, pharmaceutical compositions containingthe compounds and methods of use thereof in treating diseases modulatedby certain caspases, including but not limited to caspase-1, caspase-4and/or caspase-5. In one embodiment, the compounds for use in thecompositions and methods provided herein are of Formula I:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, X, Y, Y¹, Y² and Z³ are as defined elsewhere herein.

Also provided herein are pharmaceutical compositions comprising one ormore compound(s) of Formula I and a pharmaceutically acceptable carrier.

In one embodiment, provided herein are methods of treating a disease orcondition associated with the inflammatory caspases (i.e. caspase-1,caspase-4 and caspase-5) and/or the modulation of the inflammatorycaspases, by administering a therapeutically effective amount of acompound provided herein. Treatment can include amelioration, mitigationand/or prevention. In certain embodiments, the conditions or diseasesassociated with the inflammatory caspases and/or the modulation ofinflammatory caspases are selected from autoimmune diseases,inflammatory diseases, CNS diseases liver diseases, respiratorydiseases, cardiovascular diseases, dermatological diseases,rheumatological diseases, kidney diseases, and cancers. In certainembodiments, the conditions or diseases associated with the inflammatorycaspases and/or the modulation of inflammatory caspases are selectedfrom autoimmune diseases, inflammatory diseases, CNS diseases liverdiseases, respiratory diseases, cardiovascular diseases, dermatologicaldiseases, rheumatological diseases, kidney diseases, ophthalmologicaldiseases and cancers.

In one embodiment, provided herein are methods of treating a disease orcondition associated with caspase-1, caspase-4 and/or caspase-5 and/orthe modulation of caspase-1, caspase-4 and/or caspase-5, byadministering a therapeutically effective amount of a compound herein.Treatment can include amelioration, mitigation and/or prevention. Incertain embodiments, the conditions or diseases associated withcaspase-1, caspase-4 and/or caspase-5 and/or the modulation ofcaspase-1, caspase-4 and/or caspase-5 are selected fromautoinflammatory, autoimmune diseases, inflammatory diseases, CNSdiseases, liver diseases, respiratory diseases, cardiovascular diseases,dermatological diseases, rheumatological diseases kidney diseases, andcancer. In certain embodiments, the conditions or diseases associatedwith caspase-1, caspase-4 and/or caspase-5 and/or the modulation ofcaspase-1, caspase-4 and/or caspase-5 are selected fromautoinflammatory, autoimmune diseases, inflammatory diseases, CNSdiseases, liver diseases, respiratory diseases, cardiovascular diseases,dermatological diseases, rheumatological diseases kidney diseases,ophthalmological diseases and cancer.

In one embodiment, the compositions described herein are useful for thetreatment, prevention, or amelioration of autoinflammatory diseases,neuroinflammatory diseases, autoimmune diseases and of otherinflammatory conditions. In one embodiment, the compositions describedherein are useful for the treatment of liver diseases in particular,nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease(NAFLD), primary sclerosing cholangitis (PSC), primary biliary cirrhosis(PBC), autoimmune hepatitis (AIH) and viral hepatitis. In oneembodiment, the compositions described herein are useful for thetreatment of gastrointestinal diseases in particular, inflammatory boweldisease (IBD), ulcerative colitis (UC) and Crohn's disease. In oneembodiment, the compositions described herein are useful for thetreatment of CNS and neuroinflammatory diseases in particular multiplesclerosis (MS), Alzheimer's disease, Huntington's disease (HD),Parkinson's disease (PD) and epilepsies. The compositions describedherein are useful for the treatment of cardiovascular diseases andmetabolic diseases in particular myocardial infarction (MI),atherosclerosis, type 2 diabetes, and type 1 diabetes. In oneembodiment, the compositions described herein are useful for thetreatment of kidney diseases, in particular acute kidney injury (AKI),glomerulonephritis and lupus nephritis. In one embodiment, thecompositions described herein are useful for the treatment ofdermatological diseases, in particular psoriasis and acne. In oneembodiment, the compositions described herein are useful for thetreatment of rheumatological diseases, in particular rheumatoidarthritis (RA), osteoarthritis (OA), and gout. Exemplary specificautoimmune diseases for which a compound herein may be employed includesystemic lupus erythematosus, polychondritis, scleredoma, Wegenergranulomatosis, dermatomyositis, Steven-Johnson syndrome, endocrineophthalmopathy and Graves disease.

In one embodiment, the compositions described herein are also useful forthe treatment, prevention, or amelioration of asthma, steroid resistantasthma, pulmonary emphysema, and other obstructive or inflammatorydiseases of the airways.

In one embodiment, the compositions described herein are also useful forthe treatment, prevention, or amelioration of ophthalmological diseasessuch as retinal degenerative diseases such as age-related maculardegeneration (AMD).

In one embodiment, the compositions described herein may be used fortreatment of cancers.

In one embodiment, the present disclosure relates to the use of acompound provided herein for the treatment and/or prevention of cancers.Typically cancers include colorectal cancer (CRC), melanoma, gastriccancer (including esophageal cancer), renal cell carcinoma (RCC), breastcancer, prostate cancer, head and neck cancer, bladder cancer,hepatocellular carcinoma (HCC), ovarian cancer, cervical cancer,endometrial cancer, pancreatic cancer, neuroendocrine cancer,hematological cancers (particularly multiple myeloma, acute myeloblasticleukemia (AML), and biliary tract cancer.

In one embodiment, the compounds provide a therapy to improve thetreatment of cancer having at least a partial inflammatory basis. In oneembodiment, the compounds are useful for the treatment and/or preventionof cancer having at least a partial inflammatory basis. In anotheraspect, provided herein is a particular clinical dosage regimen for theadministration of a compound for the treatment and/or prevention ofcancer. In another aspect, the compound provided herein is administeredwith one or more therapeutic agent to a subject in need thereof (e.g., achemotherapeutic agent), and/or the subject in certain embodiments, havereceived/will receive debulking procedures in addition to theadministration of a compound herein.

In one embodiment, provided herein are methods of treating or preventingcancer in a human subject in need thereof comprising administering tothe subject a therapeutically effective amount of a compound providedherein.

In one embodiment, provided herein is a use of a compound for thepreparation of a medicament for the treatment of cancer.

In some embodiments, the compounds provided herein are used for thetreatment or prevention in in cryopyrin-associated periodic syndromes(CAPS), familial Mediterranean fever (FMF), systemic onset juvenileidiopathic arthritis (SJIA), hyperimmunoglobulin D syndrome (HIDS) andtumor necrosis factor receptor-associated periodic syndrome (TRAPS),familial cold urticaria, neonatal onset multisystem inflammatorydisease, SJIA and FMF, and Muckle Wells syndrome.

In practicing the methods, effective amounts of the compounds orcompositions containing therapeutically effective concentrations of thecompounds are administered to an individual exhibiting the symptoms ofthe disease or disorder to be treated. The amounts are effective toameliorate or eliminate one or more symptoms of the disease or disorder.

Further provided is a pharmaceutical pack or kit comprising one or morecontainers filled with one or more of the ingredients of thepharmaceutical compositions. Optionally associated with suchcontainer(s) can be a notice in the form prescribed by a governmentalagency regulating the manufacture, use or sale of pharmaceuticals orbiological products, which notice reflects approval by the agency ofmanufacture, use of sale for human administration. The pack or kit canbe labeled with information regarding mode of administration, sequenceof drug administration (e.g., separately, sequentially or concurrently),or the like.

These and other aspects of the subject matter described herein willbecome evident upon reference to the following detailed description.

5. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides a dose response study for the compound of Example 6 andreference compound IDN-7314 for inhibition of IL-1β in THP 1 cells.

FIG. 2 provides results of a dose response study for the compound ofExample 6 and reference compound IDN-7314 for Fas induced apoptosis inJurkat cells.

FIG. 3 demonstrates in vivo inhibition of inflammatory cytokines IL-1 βand IL 18 by the compound of Example 6 and reference compound MCC950.

FIG. 4 provides the effect of twice daily oral administration of thecompound of Example 6 and reference compounds on prevention of weightloss in a model of ulcerative colitis.

FIG. 5 provides the effect of twice daily oral administration of thecompound of Example 6 and reference compounds on colon histologyparameters in a model of ulcerative colitis.

6. DETAILED DESCRIPTION OF THE EMBODIMENTS 6.1. Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications are incorporated by reference in their entirety. In theevent that there is a plurality of definitions for a term herein, thosein this section prevail unless stated otherwise.

As used herein, “halogen” refers to all halogens, that is, a halogensubstituent can be chloro (Cl), fluoro (F), bromo (Br) or iodo (I).

“hydroxyl” or “hydroxy” refer to the group —OH.

“thio” refers to the group —SH.

As used herein, “lower alkyl” means an alkane-derived radical containingfrom 1 to 6 carbon atoms (unless specifically defined) that includes astraight chain alkyl or branched alkyl. As used herein, the term “alkyl”means a straight or branched C₁ to C₁₀ carbon chain such as methyl,ethyl, tert-butyl, iso-propyl, n-octyl, and the like. The straight chainor branched alkyl group is chemically feasible and attached at anyavailable point to produce a stable compound. In embodiments, a loweralkyl is a straight or branched alkyl group containing from 1-6, 1-4, or1-2, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl,t-butyl, and the like. A “substituted lower alkyl” denotes lower alkylthat is optionally independently substituted, unless indicatedotherwise, with one or more, for example, 1, 2, 3, 4 or 5, also 1, 2, or3 substituents, attached at any available atom to produce a stablecompound, wherein the substituents are selected from the groupconsisting of —F, —OH, —NH₂, —NO₂, —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH₂,—C(S)—NH₂, —S(O)₂—NH₂, —N(H)—C(O)—NH₂, —N(H)—C(S)—NH₂, —N(H)—S(O)₂—NH₂,—C(NH), —NH₂, —O—R^(o), —S—R^(o), —O—C(O)—R^(o), —O—C(S)—R^(o),—C(O)—R^(o), —C(S)—R^(o), —C(O)—O—R^(o), —C(S)—O—R^(o), —S(O)—R^(o),—S(O)₂—R^(o), —C(O)—N(H)—R^(o), —C(S)—N(H)—R^(o), —C(O)—N(R^(o))—R^(o),—C(S)—N(R^(o))—R^(o), —S(O)₂—N(H)—R^(o), —S(O)₂—N(R^(o))—R^(o),—C(NH)—N(H)—R^(o), —C(NH)—N(R^(p))—R^(c), —N(H)—C(O)—R^(o),—N(H)—C(S)—R^(o), —N(R^(o))—C(O)—R^(o), —N(R^(o))—C(S)—R^(o),—N(H)—S(O)₂—R^(o), —N(R^(o))—S(O)₂—R^(o), —N(H)—C(O)—N(H)—R^(o),—N(H)—C(S)—N(H)—R^(o), —N(R^(o))—C(O)—NH₂, —N(R^(o))—C(S)—NH₂,—N(R^(o))—C(O)—N(H)—R^(o), —N(R^(o))—C(S)—N(H)—R^(o),—N(H)—C(O)—N(R^(o))—R^(o), —N(H)—C(S)—N(R^(o))— R^(o),—N(R^(o))—C(O)—N(R^(o))—R^(o), —N(R^(o))—C(S)—N(R^(o))—R^(o),—N(H)—S(O)₂—N(H)—R^(o), —N(R^(o))—S(O)₂—NH₂, —N(R^(o))—S(O)₂—N(H)—R^(o),—N(H)—S(O)₂—N(R^(o))—R^(o), —N(R^(o))—S(O)₂—N(R^(o))—R^(o), —N(H)—R^(o),—N(R^(o))—R^(o), —R^(c), —R^(f), and —R^(g).

“Alkylene” refer to a straight or branched divalent hydrocarbon chainconsisting solely of carbon and hydrogen, containing no unsaturation.“Lower alkylene” refer to a straight or branched divalent hydrocarbonchain consisting solely of carbon and hydrogen, containing nounsaturation and having from one to six carbon atoms, e.g., methylene,ethylene, propylene, n-butylene and the like. In certain embodiment,alkylene and lower alkylene is substituted with one or more substituentdescribed in the definition of alkyl a group above.

“Lower alkenyl” alone or in combination means a straight or branchedhydrocarbon containing 2-6 carbon atoms (unless specifically defined)and at least one, 1-3, 1-2, or only one, carbon to carbon double bond.The term “alkenyl” means a straight or branched C₁ to C₁₀ carbon chaincontaining at least one, 1-3, 1-2, or only one, carbon to carbon doublebond. Carbon to carbon double bonds can either be contained within astraight chain or branched portion. The straight chain or branched loweralkenyl group is chemically feasible and attached at any available pointto provide a stable compound. Examples of lower alkenyl groups includeethenyl, propenyl, isopropenyl, butenyl, and the like. A “substitutedlower alkenyl” denotes lower alkenyl that is optionally independentlysubstituted, unless indicated otherwise, with one or more, for example,1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any availableatom to produce a stable compound, wherein the substituents are selectedfrom the group consisting of —F, —OH, —NH₂, —NO₂, —CN, —C(O)—OH,—C(S)—OH, —C(O)—NH₂, —C(S)—NH₂, —S(O)₂—NH₂, —N(H)—C(O)—NH₂,—N(H)—C(S)—NH₂, —N(H)—S(O)₂—NH₂, —C(NH)—NH₂, —O—R^(o), —S—R^(o),—O—C(O)—R^(o), —O—C(S)—R^(o), —C(O)—R^(o), —C(S)—R^(o), —C(O)—O—R^(o),—C(S)—O—R^(o), —S(O)—R^(o), —S(O)₂—R^(o), —C(O)—N(H)—R^(o),—C(S)—N(H)—R^(o), —C(O)—N(R^(o))—R^(o), —C(S)—N(R^(o))—R^(o),—S(O)₂—N(H)—R^(o), —S(O)₂—N(R^(o))—R^(o), —C(NH)—N(H)—R^(o),—C(NH)—N(R^(p))—R^(o), —N(H)—C(O)—R^(o), —N(H)—C(S)—R^(o),—N(R^(o))—C(O)—R^(o), —N(R^(o))—C(S)—R^(o), —N(H)—S(O)₂—R^(o),—N(R^(o))—S(O)₂—R^(o), —N(H)—C(O)—N(H)—R^(o), —N(H)—C(S)—N(H)—R^(o),—N(R^(o))—C(O)—NH₂, —N(R^(o))—C(S)—NH₂, —N(R^(o))—C(O)—N(H)—R^(o),—N(R^(o))—C(S)—N(H)—R^(o), —N(H)—C(O)—N(R^(o))—R^(o),—N(H)—C(S)—N(R^(o))—R^(o), —N(R^(o))—C(O)—N(R^(o))—R^(o),—N(R^(o))—C(S)—N(R^(o))—R^(o), —N(H)—S(O)₂—N(H)—R^(o),—N(R^(o))—S(O)₂—NH₂, —N(R^(o))—S(O)₂—N(H)—R^(o),—N(H)—S(O)₂—N(R^(o))—R^(o), —N(R^(o))—S(O)₂—N(R^(o))—R^(o), —N(H)—R^(o),—N(R^(o))—R^(o), —R^(d), —R^(f), and —R^(g).

“Lower alkynyl” alone or in combination means a straight or branchedhydrocarbon containing 2-6 carbon atoms (unless specifically defined)containing at least one, or only one, carbon to carbon triple bond. Theterm “alkynyl” means a straight or branched C₁ to C₁₀ carbon chaincontaining at least one, or only one, carbon to carbon triple bond. Thestraight chain or branched lower alkynyl group is chemically feasibleand attached at any available point to provide a stable compound.Examples of alkynyl groups include ethynyl, propynyl, butynyl, and thelike. A “substituted lower alkynyl” denotes lower alkynyl that isoptionally independently substituted, unless indicated otherwise, withone or more, for example, 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents,attached at any available atom to produce a stable compound, wherein thesubstituents are selected from the group consisting of —F, —OH, —NH₂,—NO₂, —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH₂, —C(S)—NH₂, —S(O)₂—NH₂,—N(H)—C(O)—NH₂, —N(H)—C(S)—NH₂, —N(H)—S(O)₂—NH₂, —C(NH)—NH₂, —O—R^(o),—S—R^(o), —O—C(O)—R^(o), —O—C(S)—R^(o), —C(O)—R^(o), —C(S)—R^(o),—C(O)—O—R^(o), —C(S)—O—R^(o), —S(O)—R^(o), —S(O)₂—R^(o),—C(O)—N(H)—R^(o), —C(S)—N(H)—R^(o), —C(O)—N(R^(o))—R^(o),—C(S)—N(R^(o))—R^(o), —S(O)₂—N(H)—R^(o), —S(O)₂—N(R^(o))—R^(o),—C(NH)—N(H)—R^(o), —C(NH)—N(R^(p))—R^(o), —N(H)—C(O)—R^(o),—N(H)—C(S)—R^(o), —N(R^(o))—C(O)—R^(o), —N(R^(o))—C(S)—R^(o),—N(H)—S(O)₂—R^(o), —N(R^(o))—S(O)₂—R^(o), —N(H)—C(O)—N(H)—R^(o),—N(H)—C(S)—N(H)—R^(o), —N(R^(o))—C(O)—NH₂, —N(R^(o))—C(S)—NH₂,—N(R^(o))—C(O)—N(H)—R^(o), —N(R^(o))—C(S)—N(H)—R^(o),—N(H)—C(O)—N(R^(o))—R^(o), —N(H)—C(S)—N(R^(o))—R^(o),—N(R^(o))—C(O)—N(R^(o))—R^(o), —N(R^(o))—C(S)—N(R^(o))—R^(o),—N(H)—S(O)₂—N(H)—R^(o), —N(R^(o))—S(O)₂—NH₂, —N(R^(o))—S(O)₂—N(H)—R^(o),—N(H)—S(O)₂—N(R^(o))—R^(o), —N(R^(o))—S(O)₂—N(R^(o))—R^(o), —N(H)—R^(o),—N(R^(o))—R^(o), —R^(d), —R^(e), and —R^(g).

“Cycloalkyl” refers to saturated or unsaturated, non-aromaticmonocyclic, bicyclic or tricyclic carbon ring systems of 3-10, also 3-8or 3-6, ring members per ring, such as cyclopropyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, cis- or trans-decalin,bicyclo[2.2.1]hept-2-ene, cyclohex-1-enyl, cyclopent-1-enyl,1,4-cyclooctadienyl and the like. The term “(cycloalkyl)alkyl” means theabove-defined alkyl group substituted with a cycloalkyl ring. Examplesof such a group include (cyclohexyl)methyl, 3-(cyclopropyl)-n-propyl,5-(cyclopentyl)hexyl, 6-(adamantyl)hexyl, and the like.

A “substituted cycloalkyl” is a cycloalkyl that is optionallyindependently substituted, unless indicated otherwise, with one or more,for example, 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached atany available atom to produce a stable compound, wherein thesubstituents are selected from the group consisting of halogen, —OH,—NH₂, —NO₂, —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH₂, —C(S)—NH₂, —S(O)₂—NH₂,—N(H)—C(O)—NH₂, —N(H)—C(S)—NH₂, —N(H)—S(O)₂—NH₂, —C(NH)—NH₂, —O—R^(o),—S—R^(o), —O—C(O)—R^(o), —O—C(S)—R^(o), —C(O)—R^(o), —C(S)—R^(o),—C(O)—O—R^(o), —C(S)—O—R^(o), —S(O)—R^(o), —S(O)₂—R^(o),—C(O)—N(H)—R^(o), —C(S)—N(H)—R^(o), —C(O)—N(R^(o))—R^(o),—C(S)—N(R^(o))—R^(o), —S(O)₂—N(H)—R^(o), —S(O)₂—N(R^(o))—R^(o),—C(NH)—N(H)—R^(o), —C(NH)—N(R^(p))—R^(o), —N(H)—C(O)—R^(o),—N(H)—C(S)—R^(o), —N(R^(o))—C(O)—R^(o), —N(R^(o))—C(S)—R^(o),—N(H)—S(O)₂—R^(o), —N(R^(o))—S(O)₂—R^(o), —N(H)—C(O)—N(H)—R^(o),—N(H)—C(S)—N(H)—R^(o), —N(R^(o))—C(O)—NH₂, —N(R^(o))—C(S)—NH₂,—N(R^(o))—C(O)—N(H)—R^(o), —N(R^(o))—C(S)—N(H)—R^(o),—N(H)—C(O)—N(R^(o))—R^(o), —N(H)—C(S)—N(R^(o))—R^(o),—N(R^(o))—C(O)—N(R^(o))—R^(o), —N(R^(o))—C(S)—N(R^(o))—R^(o),—N(H)—S(O)₂—N(H)—R^(o), —N(R^(o))—S(O)₂—NH₂, —N(R^(o))—S(O)₂—N(H)—R^(o),—N(H)—S(O)₂—N(R^(o))—R^(o), —N(R^(o))—S(O)₂—N(R^(o))—R^(o), —N(H)—R^(o),—N(R^(o))—R^(o), —R^(d), —R^(e), —R^(f), and —R^(g). For example, “C₃₋₆cycloalkyl” denotes cycloalkyl containing 3-6 carbon atoms, and “C₃₋₅cycloalkyl” denotes cycloalkyl containing 3-5 carbon atoms.

“Heterocycloalkyl” refers to a saturated or unsaturated non-aromaticcycloalkyl group containing from 5 to 10 atoms in which from 1 to 3carbon atoms in the ring are replaced by heteroatoms of O, S or N, andoptionally are fused with benzo or heteroaryl of 5-6 ring members.Heterocycloalkyl is also intended to include oxidized S or N, such assulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen.Heterocycloalkyl is also intended to include compounds in which a ringcarbon can be oxo substituted, i.e., the ring carbon is a carbonylgroup, such as lactones and lactams. The point of attachment of theheterocycloalkyl ring is at a carbon or nitrogen atom such that a stablering is retained. Examples of heterocycloalkyl groups include, but arenot limited to, morpholino, tetrahydrofuranyl, dihydropyridinyl,piperidinyl, pyrrolidinyl, pyrrolidonyl, piperazinyl, dihydrobenzofuryl,and dihydroindolyl. “Nitrogen containing heterocycloalkyl” refers toheterocycloalkyl wherein at least one heteroatom is N. The term“(heterocycloalkyl)alkyl” means the above-defined alkyl groupsubstituted with a heterocycloalkyl ring.

A “substituted heterocycloalkyl” is a heterocycloalkyl that isoptionally independently substituted, unless indicated otherwise, withone or more, for example, 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents,attached at any available atom to produce a stable compound, wherein thesubstituents are selected from the group consisting of halogen, —OH,—NH₂, —NO₂, —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH₂, —C(S)—NH₂, —S(O)₂—NH₂,—N(H)—C(O)—NH₂, —N(H)—C(S)—NH₂, —N(H)—S(O)₂—NH₂, —C(NH)—NH₂, —O—R^(o),—S—R^(o), —O—C(O)—R^(o), —O—C(S)—R^(o), —C(O)—R^(o), —C(S)—R^(o),—C(O)—O—R^(o), —C(S)—O—R^(o), —S(O)—R^(o), —S(O)₂—R^(o),—C(O)—N(H)—R^(o), —C(S)—N(H)—R^(o), —C(O)—N(R^(o))—R^(o),—C(S)—N(R^(o))—R^(o), —S(O)₂—N(H)—R^(o), —S(O)₂—N(R^(o))—R^(o),—C(NH)—N(H)—R^(o), —C(NH)—N(R^(p))—R^(o), —N(H)—C(O)—R^(o),—N(H)—C(S)—R^(o), —N(R^(o))—C(O)—R^(o), —N(R^(o))—C(S)—R^(o),—N(H)—S(O)₂—R^(o), —N(R^(o))—S(O)₂—R^(o), —N(H)—C(O)—N(H)—R^(o),—N(H)—C(S)—N(H)—R^(o), —N(R^(o))—C(O)—NH₂, —N(R^(o))—C(S)—NH₂,—N(R^(o))—C(O)—N(H)—R^(o), —N(R^(o))—C(S)—N(H)—R^(o),—N(H)—C(O)—N(R^(o))—R^(o), —N(H)—C(S)—N(R^(o))—R^(o),—N(R^(o))—C(O)—N(R^(o))—R^(o), —N(R^(o))—C(S)—N(R^(o))—R^(o),—N(H)—S(O)₂—N(H)—R^(o), —N(R^(o))—S(O)₂—NH₂, —N(R^(o))—S(O)₂—N(H)—R^(o),—N(H)—S(O)₂—N(R^(o))—R^(o), —N(R^(o))—S(O)₂—N(R^(o))—R^(o), —N(H)—R^(o),—N(R^(o))—R^(o), —R^(d), —R^(e), —R^(f), and —R^(g).

“Aryl” alone or in combination refers to a monocyclic or bicyclic ringsystem containing aromatic hydrocarbons such as phenyl or naphthyl,which optionally can be fused with a cycloalkyl of, for example, 5-7,or, for example, 5-6, ring members. A “substituted aryl” is an aryl thatoptionally is independently substituted, unless indicated otherwise,with one or more, for example, 1, 2, 3, 4 or 5, also 1, 2, or 3substituents, attached at any available atom to produce a stablecompound, wherein the substituents are selected from the groupconsisting of halogen, —OH, —NH₂, —NO₂, —CN, —C(O)—OH, —C(S)—OH,—C(O)—NH₂, —C(S)—NH₂, —S(O)₂—NH₂, —N(H)—C(O)—NH₂, —N(H)—C(S)—NH₂,—N(H)—S(O)₂—NH₂, —C(NH)—NH₂, —O—R^(o), —S—R^(o), —O—C(O)—R^(o),—O—C(S)—R^(o), —C(O)—R^(o), —C(S)—R^(o), —C(O)—O—R^(o), —C(S)—O—R^(o),—S(O)—R^(o), —S(O)₂—R^(o), —C(O)—N(H)—R^(o), —C(S)—N(H)—R^(o),—C(O)—N(R^(o))—R^(o), —C(S)—N(R^(o))—R^(o), —S(O)₂—N(H)—R^(o),—S(O)₂—N(R^(o))—R^(o), —C(NH)—N(H)—R^(o), —C(NH)—N(R^(p))—R^(o),—N(H)—C(O)—R^(o), —N(H)—C(S)—R^(o), —N(R^(o))—C(O)—R^(o),—N(R^(o))—C(S)—R^(o), —N(H)—S(O)₂—R^(o), —N(R^(o))—S(O)₂—R^(o),—N(H)—C(O)—N(H)—R^(o), —N(H)—C(S)—N(H)—R^(o), —N(R^(o))—C(O)—NH₂,—N(R^(o))—C(S)—NH₂, —N(R^(o))—C(O)—N(H)—R^(o),—N(R^(o))—C(S)—N(H)—R^(o), —N(H)—C(O)—N(R^(o))—R^(o),—N(H)—C(S)—N(R^(o))—R^(o), —N(R^(o))—C(O)—N(R^(o))—R^(o),—N(R^(o))—C(S)—N(R^(o))—R^(o), —N(H)—S(O)₂—N(H)—R^(o),—N(R^(o))—S(O)₂—NH₂, —N(R^(o))—S(O)₂—N(H)—R^(o),—N(H)—S(O)₂—N(R^(o))—R^(o), —N(R^(o))—S(O)₂—N(R^(o))—R^(o), —N(H)—R^(o),—N(R^(o))—R^(o), —R^(d), —R^(e), —R^(f), and —R^(g). In someembodiments, the substituents are selected from among one to three halo,trihalomethyl, amino, protected amino, amino salts, mono-substitutedamino, di-substituted amino, carboxy, protected carboxy, carboxylatesalts, hydroxy, protected hydroxy, salts of a hydroxy group, loweralkoxy, lower alkylthio, lower alkyl, substituted lower alkyl,cycloalkyl, substituted cycloalkyl, (cycloalkyl)alkyl, substituted(cycloalkyl)alkyl, phenyl, substituted phenyl, phenylalkyl, andsubstituted phenylalkyl groups. In certain embodiments, the substituentsare selected from among trifluoromethyl, trichloromethyl, tribromomethyland triiodomethyl. In some embodiments, the substituents are one or moretrifluoromethyl.

The term “substituted phenyl” specifies a phenyl group substituted withone or more substituents chosen from the above-identified “aryl”substituents. In embodiments, the substituents are selected from amonghalogen, hydroxy, protected hydroxy, cyano, nitro, trifluoromethyl,alkyl, alkoxy, acyl, acyloxy, carboxy, protected carboxy, carboxymethyl,protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino,protected amino, (monosubstituted)amino, protected(monosubstituted)amino, (disubstituted) amino, carboxamide, protectedcarboxamide, N-(lower alkyl)carboxamide, protected N-(loweralkyl)carboxamide, N,N-di(lower alkyl)carboxamide, N-((loweralkyl)sulfonyl) amino, N-(phenylsulfonyl)amino or by a substituted orunsubstituted phenyl group, such that in the latter case a biphenyl ornaphthyl group results. Examples of the term “substituted phenyl”include a mono-, di-, tri- or tetra(halo)phenyl group such as 2-, 3- or4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl,3,4-dichlorophenyl, 2,3,5-trichlorophenyl, 2,3,5,6-tetrachlorophenyl,2-, 3- or 4-bromophenyl, 2,6-dibromophenyl, 2,5-dibromophenyl,3,4-dibromophenyl, 2,3,5-tribromophenyl, 2,3,5,6-tetrabromophenyl, 2-,3- or 4-fluorophenyl, 2,6-difluorophenyl, 2,5-difluorophenyl,3,4-difluorophenyl, 2,3,5-trifluorophenyl, 2,3,5,6-tetrafluorophenyl,3-chloro-4-fluorophenyl and the like; a mono or di(hydroxy)phenyl groupsuch as 2-, 3-, or 4-hydroxyphenyl, 2,4-dihydroxyphenyl, theprotected-hydroxy derivatives thereof and the like; a nitrophenyl groupsuch as 2-, 3-, or 4-nitrophenyl; a cyanophenyl group, for example, 2-,3- or 4-cyanophenyl; a mono- or di(alkyl)phenyl group such as 2-, 3-, or4-methylphenyl, 2,4-dimethylphenyl, 2-, 3- or 4-(isopropyl)phenyl, 2-,3-, or 4-ethylphenyl, 2-, 3- or 4-(n-propyl)phenyl and the like; a monoor di(alkoxy)phenyl group, for example, 2,6-dimethoxyphenyl, 2-, 3- or4-(isopropoxy)phenyl, 2-, 3- or 4-(t-butoxy)phenyl,3-ethoxy-4-methoxyphenyl and the like; 2-, 3- or4-trifiuoromethylphenyl; a mono- or dicarboxyphenyl or (protectedcarboxyphenyl group such as 2-, 3- or 4-carboxyphenyl or2,4-di(protected carboxy)phenyl; a mono- or di(hydroxymethyl)phenyl or(protected hydroxymethyl)phenyl such as 2-, 3- or 4-(protectedhydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; a mono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as 2-, 3- or4-(aminomethyl) phenyl or 2,4-(protected aminomethyl)phenyl; or a mono-or di(N-(methylsulfonylamino))phenyl such as 2, 3 or4-(N(methylsulfonylamino))phenyl. Also, the term “substituted phenyl”represents disubstituted phenyl groups wherein the substituents aredifferent, for example, 3-methyl-4-hydroxyphenyl,3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl,4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl,2-hydroxy-4-chlorophenyl, and the like.

The term “arylalkyl” means an aryl groups attached to one of theabove-described alkyl groups, and the term “substituted arylalkyl” meansthat either the aryl, or the alkyl, or both, are substituted with one ormore of the above-defined substituents. Examples of “arylalkyl”substituents include, for example, phenylmethyl (benzyl), phenylethyl,phenylpropyl, phenylisopropyl and the like. Examples of “substitutedphenyl” groups include 2-phenyl-1-chloroethyl,2-(4′-methoxyphenyl)ethyl, 4-(2′,6′-dihydroxy phenyl)n-hexyl,2-(5′-cyano-3′ methoxyphenyl)n-pentyl, 3-(2′,6′-dimethylphenyl)n-propyl,4-chloro-3-aminobenzyl, 6-(4′-methoxyphenyl)-3-carboxy (n-hexyl),5-(4′-aminomethylphenyl)-3-(aminomethyl)n-pentyl,5-phenyl-3-oxo-n-pent-1-yl, (4-hydroxynapth-2-yl)methyl, and the like.

“Heteroaryl” alone or in combination refers to a monocyclic aromaticring structure containing 5 or 6 ring atoms, or a bicyclic aromaticgroup having 8 to 10 atoms, containing one or more, e.g., 1-4, 1-3 or1-2 heteroatoms independently selected from the group consisting of O,S, and N, which optionally can be fused with a cycloalkyl of, forexample, 5-7, or, for example, 5-6, ring members. Heteroaryl also isintended to include oxidized S or N, such as sulfinyl, sulfonyl andN-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is thepoint of attachment of the heteroaryl ring structure such that a stablecompound is produced. Examples of heteroaryl groups (whether substitutedor unsubstituted) include, but are not limited to, pyridinyl,pyridazinyl, pyrazinyl, quinoxalyl, indolizinyl, benzo [b]thienyl,quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl,pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl,isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, pyrrolidinyl,thiadiazolyl, oxadiazolyl, thiatriazolyl, oxatriazolyl, pyridyl,oxazinyl, triazinyl, thiadiazinyl tetrazolo, 1,5-[b]pyridazinyl andpurinyl, as well as benzo-fused derivatives, for example, benzoxazolyl,benzothiazolyl, benzimidazolyl, benzofuryl and indolyl. “Nitrogencontaining heteroaryl” refers to heteroaryl wherein at least oneheteroatom is N. In some instances, for example when R groups of anitrogen combine with the nitrogen to form a 5 or 7 membered nitrogencontaining heteroaryl, any heteroatoms in such 5 or 7 memberedheteroaryl are N. An “optionally substituted heteroaryl” is a heteroarylthat is optionally independently substituted, unless indicatedotherwise, with one or more, for example, 1, 2, 3, 4 or 5, also 1, 2, or3 substituents, attached at any available atom to produce a stablecompound, wherein the substituents are selected from the groupconsisting of halogen, —CF₃, —OH, —NH₂, —NO₂, —CN, —C(O)—OH, —C(S)—OH,—C(O)—NH₂, —C(S)—NH₂, —S(O)₂—NH₂, —N(H)—C(O)—NH₂, —N(H)—C(S)—NH₂,—N(H)—S(O)₂—NH₂, —C(NH)—NH₂, —O—R^(o), —S—R^(o), —O—C(O)—R^(o),—O—C(S)—R^(o), —C(O)—R^(o), —C(S)—R^(o), —C(O)—O—R^(o), —C(S)—O—R^(o),—S(O)—R^(o), —S(O)₂—R^(o), —C(O)—N(H)—R^(o), —C(S)—N(H)—R^(o),—C(O)—N(R^(o))—R^(o), —C(S)—N(R^(o))—R^(o), —S(O)₂—N(H)—R^(o),—S(O)₂—N(R^(o))—R^(o), —C(NH)—N(H)—R^(o), —C(NH)—N(R^(p))—R^(o),—N(H)—C(O)—R^(o), —N(H)—C(S)—R^(o), —N(R^(o))—C(O)—R^(o),—N(R^(o))—C(S)—R^(o), —N(H)—S(O)₂—R^(o), —N(R^(o))—S(O)₂—R^(o),—N(H)—C(O)—N(H)—R^(o), —N(H)—C(S)—N(H)—R^(o), —N(R^(o))—C(O)—NH₂,—N(R^(o))—C(S)—NH₂, —N(R^(o))—C(O)—N(H)—R^(o),—N(R^(o))—C(S)—N(H)—R^(o), —N(H)—C(O)—N(R^(o))—R^(o),—N(H)—C(S)—N(R^(o))—R^(o), —N(R^(o))—C(O)—N(R^(o))—R^(o),—N(R^(o))—C(S)—N(R^(o))—R^(o), —N(H)—S(O)₂—N(H)—R^(o),—N(R^(o))—S(O)₂—NH₂, —N(R^(o))—S(O)₂—N(H)—R^(o),—N(H)—S(O)₂—N(R^(o))—R^(o), —N(R^(o))—S(O)₂—N(R^(o))—R^(o), —N(H)—R^(o),—N(R^(o))—R^(o), —R^(d), —R^(e), —R^(f), and —R^(g).

Substituents for the above optionally substituted heteroaryl rings areas denoted above, e.g., for the “aryl,” and “phenyl,” groups. In certainembodiments, the substituents are selected from among one to three halo,trihalomethyl, amino, protected amino, amino salts, mono-substitutedamino, di-substituted amino, carboxy, protected carboxy, carboxy latesalts, hydroxy, protected hydroxy, salts of a hydroxy group, loweralkoxy, lower alkylthio, lower alkyl, substituted lower alkyl,cycloalkyl, substituted cycloalkyl, (cycloalkyl)alkyl, substituted(cycloalkyl)alkyl, phenyl, substituted phenyl, phenylalkyl, andsubstituted phenylalkyl groups.

“Pyridyl,” as used herein, refers to a 6-membered aromatic ring with one“N” atom. As used herein, “pyridazinyl” refers to a 6-membered aromaticring with two “N” atoms in the 1 and 2 positions, “pyrimidyl” refers toa 6-membered aromatic ring with two “N” atoms in the 1 and 3 positionsand “pyrazinyl” refers to a 6-membered aromatic ring with two “N” atomsin the 1 and 4 positions.

Substituents for the above defined “pyridyl,” “pyridazinyl,” “pyrimidyl”and “pyrazinyl” groups are as denoted above, e.g., for the “aryl,”“phenyl,” and “heteroaryl” groups. In some embodiments, the substituentsare selected from among one to three halo, trihalomethyl, amino,protected amino, amino salts, mono-substituted amino, di-substitutedamino, carboxy, protected carboxy, carboxylate salts, hydroxy, protectedhydroxy, salts of a hydroxy group, lower alkoxy, lower alkylthio, loweralkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl,(cycloalkyl)alkyl, substituted (cycloalkyl)alkyl, phenyl, substitutedphenyl, phenylalkyl, and substituted phenylalkyl groups. In certainembodiments, the substituents are selected from among trifluoromethyl,trichloromethyl, tribromomethyl and triiodomethyl. In some embodiments,the substituents are one or more trifluoromethyl.

The variables R^(o), R^(p), R^(c), R^(d), R^(e), R^(f) and R^(g) as usedin the description of optional substituents for alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, phenyl, napthyl and heteroaryl aredefined as follows:

-   -   each R^(o), R^(p), and R are independently selected from the        group consisting of R^(d), R^(e), R^(f), and R^(g), or R^(p) and        R^(c) combine with the nitrogen to which they are attached to        form a 5-7 membered heterocycloalkyl or a 5 or 7 membered        nitrogen containing heteroaryl, wherein the 5-7 membered        heterocycloalkyl or 5 or 7 membered nitrogen containing        heteroaryl are optionally substituted with one or more, for        example 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected        from the group consisting of halogen, —NO₂, —CN, —OH, —NH₂,        —O—R^(u), —S—R^(u), —N(H)—R^(u), —N(R^(u))—R^(u), —R^(x), and        —R^(y);    -   each R^(d) is independently lower alkyl, wherein lower alkyl is        optionally substituted with one or more, for example 1, 2, 3, 4        or 5, also 1, 2 or 3 substituents selected from the group        consisting of fluoro, —OH, —NH₂, —NO₂, —CN, —C(O)—OH, —C(S)—OH,        —C(O)—NH₂, —C(S)—NH₂, —S(O)₂—NH₂, —N(H)—C(O)—NH₂,        —N(H)—C(S)—NH₂, —N(H)—S(O)₂—NH₂, —C(NH)—NH₂, —O—R^(k), —S—R^(k),        —O—C(O)—R^(k), —O—C(S)—R^(k), —C(O)—R^(k), —C(S)—R^(k),        —C(O)—O—R^(k), —C(S)—O—R^(k), —S(O)—R^(k), —S(O)₂R^(k),        —C(O)—N(H)—R^(k), —C(S)—N(H)—R^(k), —C(O)—N(R^(k))—R^(k),        —C(S)—N(R^(k))—R^(k), —S(O)₂—N(H)—R^(k), —S(O)₂N(R^(k))—R^(k),        —C(NH)—N(H)—R^(k), —C(NH)—N(R^(m))—R^(n), —N(H)—C(O)—R^(k),        —N(H)—C(S)—R^(k), —N(R^(k))—C(O)—R^(k), —N(R^(k))—C(S)—R^(k),        —N(H)—S(O)₂—R^(k), —N(R^(k))—S(O)₂—R^(k), —N(H)—C(O)—N(H) R^(k),        —N(H)—C(S)—N(H)—R^(k), —N(R^(k))—C(O)—NH₂, —N(R^(k))—C(S)—NH₂,        —N(R^(k))—C(O)—N(H)—R^(k), —N(R^(k))—C(S)—N(H)—R^(k),        —N(H)—C(O)—N(R^(k))—R^(k), —N(H)—C(S)—N(R^(k))—R^(k),        —N(R^(k))—C(O)—N(R^(k))—R^(k), —N(R^(k))—C(S)—N(R^(k))—R^(k),        —N(H)—S(O)₂—N(H)—R^(k), —N(R^(k))—S(O)₂—NH₂,        —N(R^(k))—S(O)₂—N(H)—R^(k), —N(H)—S(O)₂—N(R^(k))—R^(k),        —N(R^(k))—S(O)₂—N(R^(k))—R^(k), —N(H)—R^(k), —N(R^(k))—R^(k),        —R^(i), and —R^(j);    -   each R^(e) is independently lower alkenyl, wherein lower alkenyl        is optionally substituted with one or more, for example 1, 2, 3,        4 or 5, also 1, 2 or 3 substituents selected from the group        consisting of fluoro, —OH, —NH₂, —NO₂, —CN, —C(O)—OH, —C(S)—OH,        —C(O)—NH₂, —C(S)—NH₂, —S(O)₂—NH₂, —N(H)—C(O)—NH₂,        —N(H)—C(S)—NH₂, —N(H)—S(O)₂—NH₂, —C(NH)—NH₂, —O—R^(k), —S—R^(k),        —O—C(O)—R^(k), —O—C(S)—R^(k), —C(O)—R^(k), —C(S)—R^(k),        —C(O)—O—R^(k), —C(S)—O—R^(k), —S(O)—R^(k), —S(O)₂—R^(k),        —C(O)—N(H)—R^(k), —C(S)—N(H)—R^(k), —C(O)—N(R^(k))—R^(k),        —C(S)—N(R^(k))—R^(k), —S(O)₂—N(H)—R^(k), —S(O)₂N(R^(k))—R^(k),        —C(NH)—N(H)—R^(k), —C(NH)—N(R^(m))—R^(n), —N(H)—C(O)—R^(k),        —N(H)—C(S)—R^(k), —N(R^(k))—C(O)—R^(k), —N(R^(k))—C(S)—R^(k),        —N(H)—S(O)₂—R^(k), —N(R^(k))—S(O)₂—R^(k), —N(H)—C(O)—N(H)—R^(k),        —N(H)—C(S)—N(H)—R^(k), —N(R^(k))—C(O)—NH₂, —N(R^(k))—C(S)—NH₂,        —N(R^(k))—C(O)—N(H)—R^(k), —N(R^(k))—C(S)—N(H)—R^(k),        —N(H)—C(O)—N(R^(k))—R^(k), —N(H)—C(S)—N(R^(k))—R^(k),        —N(R^(k))—C(O)—N(R^(k))—R^(k), —N(R^(k))—C(S)—N(R^(k))—R^(k),        —N(H)—S(O)₂—N(H)—R^(k), —N(R^(k))—S(O)₂—NH₂,        —N(R^(k))—S(O)₂—N(H)—R^(k), —N(H)—S(O)₂—N(R^(k))—R^(k),        —N(R^(k))—S(O)₂—N(R^(k))—R^(k), —N(H)—R^(k), —N(R^(k))—R^(k),        —R^(h), and —R^(j);    -   each R^(f) is independently lower alkynyl, wherein lower alkynyl        is optionally substituted with one or more, for example 1, 2, 3,        4 or 5, also 1, 2 or 3 substituents selected from the group        consisting of fluoro, —OH, —NH₂, —NO₂, —CN, —C(O)—OH, —C(S)—OH,        —C(O)—NH₂, —C(S)—NH₂, —S(O)₂—NH₂, —N(H)—C(O)—NH₂,        —N(H)—C(S)—NH₂, —N(H)—S(O)₂—NH₂, —C(NH)—NH₂, —O—R^(k), —S—R^(k),        —O—C(O)—R^(k), —O—C(S)—R^(k), —C(O)—R^(k), —C(S)—R^(k),        —C(O)—O—R^(k), —C(S)—O—R^(k), —S(O)—R^(k), —S(O)₂R^(k),        —C(O)—N(H)—R^(k), —C(S)—N(H)—R^(k), —C(O)—N(R^(k))—R^(k),        —C(S)—N(R^(k))—R^(k), —S(O)₂—N(H)—R^(k), —S(O)₂N(R^(k))—R^(k),        —C(NH)—N(H)—R^(k), —C(NH)—N(R^(m))—R^(n), —N(H)—C(O)—R^(k),        —N(H)—C(S)—R^(k), —N(R^(k))—C(O)—R^(k), —N(R^(k))—C(S)—R^(k),        —N(H)—S(O)₂—R^(k), —N(R^(k))—S(O)₂—R^(k), —N(H)—C(O)—N(H) R^(k),        —N(H)—C(S)—N(H)—R^(k), —N(R^(k))—C(O)—NH₂, —N(R^(k))—C(S)—NH₂,        —N(R^(k))—C(O)—N(H)—R^(k), —N(R^(k))—C(S)—N(H)—R^(k),        —N(H)—C(O)—N(R^(k))—R^(k), —N(H)—C(S)—N(R^(k))—R^(k),        —N(R^(k))—C(O)—N(R^(k))—R^(k), —N(R^(k))—C(S)—N(R^(k))—R^(k),        —N(H)—S(O)₂—N(H)—R^(k), —N(R^(k))—S(O)₂—NH₂,        —N(R^(k))—S(O)₂—N(H)—R^(k), —N(H)—S(O)₂—N(R^(k))—R^(k),        —N(R^(k))—S(O)₂—N(R^(k))—R^(k), —N(H)—R^(k), —N(R^(k))—R^(k),        —R^(h), and —R^(j);    -   each R^(g) is independently selected from the group consisting        of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are        optionally substituted with one or more, for example 1, 2, 3, 4        or 5, also 1, 2 or 3 substituents selected from the group        consisting of halogen, —OH, —NH₂, —NO₂, —CN, —C(O)—OH, —C(S)—OH,        —C(O)—NH₂, —C(S)—NH₂, —S(O)₂—NH₂, —N(H)—C(O)—NH₂,        —N(H)—C(S)—NH₂, —N(H)—S(O)₂—NH₂, —C(NH)—NH₂, —O—R^(k),        —O—C(O)—R^(k), —O—C(S)—R^(k), —C(O)—R^(k), —C(S)—R^(k),        —C(O)—O—R^(k), —C(S)—O—R^(k), —S(O)—R^(k), —S(O)₂R^(k),        —C(O)—N(H)—R^(k), —C(S)—N(H)—R^(k), —C(O) N(R^(k))—R^(k),        —C(S)—N(R^(k))—R^(k), —S(O)₂—N(H)—R^(k), —S(O)₂N(R^(k))—R^(k),        —C(NH)—N(H)—R^(k), —C(NH)—N(R^(m))—R^(n), —N(H)—C(O)—R^(k),        —N(H)—C(S)—R^(k), —N(R^(k))—C(O) R^(k), —N(R^(k))—C(S)—R^(k),        —N(H)—S(O)₂—R^(k), —N(R^(k))—S(O)₂—R^(k), —N(H)—C(O)—N(H)—R^(k),        —N(H)—C(S)—N(H)—R^(k), —N(R^(k))—C(O)—NH₂, —N(R^(k))—C(S)—NH₂,        —N(R^(k))—C(O)—N(H)—R^(k), —N(R^(k))—C(S)—N(H)—R^(k),        —N(H)—C(O)—N(R^(k))—R^(k), —N(H)—C(S)—N(R^(k))—R^(k),        —N(R^(k))—C(O)—N(R^(k))—R^(k), —N(R^(k))—C(S)—N(R^(k))—R^(k),        —N(H)—N(H)—S(O)₂N(H)—R^(k), —N(R^(k))—S(O)₂—NH₂,        —N(R^(k))—S(O)₂—N(H)—R^(k), —N(H) S(O)₂—N(R^(k))—R^(k),        —N(R^(k)) S(O)₂—N(R^(k))—R^(k), —N(H)—R^(k), —N(R^(k))—R^(k),        —R^(h), —R^(i), and —R^(j);        -   wherein R^(k), R^(m), and R^(n) at each occurrence are            independently selected from the group consisting of R^(h),            R^(i), and R^(j), or R^(m) and R^(n) combine with the            nitrogen to which they are attached to form a 5-7 membered            heterocycloalkyl or a 5 or 7 membered nitrogen containing            heteroaryl, wherein the 5-7 membered heterocycloalkyl or 5            or 7 membered nitrogen containing heteroaryl are optionally            substituted with one or more, for example 1, 2, 3, 4 or 5,            also 1, 2, or 3 substituents selected from the group            consisting of halogen, —NO₂, —CN, —OH, —NH₂, —O—R^(u),            —S—R^(u), —N(H)—R^(u), —NR^(u)R^(u), —R^(x), and —R^(y);        -   wherein each R^(h) is independently lower alkyl optionally            substituted with one or more, for example 1, 2, 3, 4 or 5,            also 1, 2, or 3 substituents selected from the group            consisting of fluoro, —OH, —NH₂, —NO₂, —CN, —C(O)—OH,            —C(S)—OH, —C(O)—NH₂, —C(S)—NH₂, —S(O)₂—NH₂, —N(H)—C(O)—NH₂,            —N(H)—C(S)—NH₂, —N(H)—S(O)₂—NH₂, —C(NH)—NH₂, —O—R^(r),            —S—R^(r), —O—C(O)—R^(r), —O—C(S)—R^(r), —C(O)—R^(r),            —C(S)—R^(r), C(O)—O—R^(r), —C(S)—O—R^(o), —S(O)—R^(o),            —S(O)₂—R^(r), —C(O)—N(H)—R^(r), —C(S)—N(H)—R^(r),            —C(O)—N(R^(r))—R^(r), —C(S)—N(R^(r))—R^(r),            —S(O)₂—N(H)—R^(r), —S(O)₂—N(R^(r))—R^(r), —C(NH)—N(H)—R^(r),            —C(NH)—N(R^(s))—R^(t), —N(H)—C(O)—R^(r), —N(H)—C(S)—R^(r),            —N(R^(r))—C(O)—R^(r), —N(R^(r))—C(S)—R^(r),            —N(H)—S(O)₂—R^(r), —N(R^(r))—S(O)₂—R^(r),            —N(H)—C(O)—N(H)—R^(r), —N(H)—C(S)—N(H)—R^(r),            —N(R^(r))—C(O)—NH₂, —N(R^(r))—C(S)—NH₂,            —N(R^(r))—C(O)—N(H)—R^(r), —N(R^(r))—C(S)—N(H)—R^(r),            —N(H)—C(O)—N(R^(r))—R^(r), —N(H)—C(S)—N(R^(r))—R^(r),            —N(R^(r))—C(O)—N(R^(r))—R^(r),            —N(R^(r))—C(S)—N(R^(r))—R^(r), —N(H)—S(O)₂—N(H)—R^(r),            —N(R^(r))—S(O)₂—NH₂, —N(R^(r))—S(O)₂—N(H)—R^(r),            —N(H)—S(O)₂—N(R^(r))—R^(r), —N(R^(r))—S(O)₂—N(R^(r))—R^(r),            —N(H)—R^(r), —N(R^(r))—R^(r), —R^(i), and —R^(j);        -   wherein each R^(i) is independently selected from the group            consisting of lower alkenyl and lower alkynyl, wherein lower            alkenyl or lower alkynyl are optionally substituted with one            or more, for example 1, 2, 3, 4 or 5, also 1, 2 or 3            substituents selected from the group consisting of fluoro,            —OH, —NH₂, —NO₂, —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH₂,            —C(S)—NH₂, —S(O)₂—NH₂, —N(H)—C(O)—NH₂, —N(H)—C(S)—NH₂,            —N(H)—S(O)₂—NH₂, —C(NH)—NH₂, —O—R^(r), —S—R^(r),            —O—C(O)—R^(r), —O—C(S)—R^(r), —C(O)—R^(r), —C(S)—R^(r),            —C(O)—O—R^(r), —C(S)—O—R^(r), —S(O)—R^(r), —S(O)₂—R^(r),            —C(O)—N(H)—R^(r), —C(S)—N(H)—R^(r), —C(O)—N(R^(r))—R^(r),            —C(S)—N(R^(r))—R^(r), —S(O)₂—N(H)—R^(r),            —S(O)₂—N(R^(r))—R^(r), —C(NH)—N(H)—R^(r),            —C(NH)—N(R^(s))—R^(t), —N(H)—C(O)—R^(r), —N(H)—C(S)—R^(r),            —N(R^(r))—C(O)—R^(r), —N(R^(r))—C(S)—R^(r),            —N(H)—S(O)₂—R^(r), —N(R^(r))—S(O)₂—R^(r),            —N(H)—C(O)—N(H)—R^(r), —N(H)—C(S)—N(H)—R^(r),            —N(R^(r))—C(O)—NH₂, —N(R^(r))—C(S)—NH₂,            —N(R^(r))—C(O)—N(H)—R^(r), —N(R^(r))—C(S)—N(H)—R^(r),            —N(H)—C(O)—N(R^(r))—R^(r), —N(H)—C(S)—N(R^(r))—R^(r),            —N(R^(r))—C(O)—N(R^(r))—R^(r),            —N(R^(r))—C(S)—N(R^(r))—R^(r), —N(H)—S(O)₂—N(H)—R^(r),            —N(R^(r))—S(O)₂—NH₂, —N(R^(r))—S(O)₂—N(H)—R^(r),            —N(H)—S(O)₂—N(R^(r))—R^(r), —N(R^(r))—S(O)₂—N(R^(r))—R^(r),            —N(H)—R^(r), —N(R^(r))—R^(r), and —R^(j);        -   wherein each R^(j) is independently selected from the group            consisting of cycloalkyl, heterocycloalkyl, aryl, and            heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and            heteroaryl are optionally substituted with one or more, for            example 1, 2, 3, 4 or 5, also 1, 2 or 3 substituents            selected from the group consisting of halogen, —OH, —NH₂,            —NO₂, —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH₂, —C(S)—NH₂,            —S(O)₂—NH₂, —N(H)—C(O)—NH₂, —N(H)—C(S)—NH₂, —N(H)—S(O)₂—NH₂,            —C(NH)—NH₂, —O—R^(r), —S—R^(r), —O—C(O)—R^(r),            —O—C(S)—R^(r), —C(O)—R^(r), —C(S)—R^(r), —C(O)—O—R^(r),            —C(S)—O—R^(r), —S(O)—R^(r), —S(O)₂—R^(r), —C(O)—N(H)—R^(r),            —C(S)—N(H)—R^(r), —C(O)—N(R^(r))—R^(r),            —C(S)—N(R^(r))—R^(r), —S(O)₂—N(H)—R^(r),            —S(O)₂—N(R^(r))—R^(r), —C(NH)—N(H)—R^(r),            —C(NH)—N(R^(s))—R^(t), —N(H)—C(O)—R^(r), —N(H)—C(S)—R^(r),            —N(R^(r))—C(O)—R^(r), —N(R^(r))—C(S)—R^(r),            —N(H)—S(O)₂—R^(r), —N(R^(r))—S(O)₂-le,            —N(H)—C(O)—N(H)—R^(r), —N(H)—C(S)—N(H)—R^(r),            —N(R^(r))—C(O)—NH₂, —N(R^(r))—C(S)—NH₂,            —N(R^(r))—C(O)—N(H)—R^(r), —N(R^(r))—C(S)—N(H)—R^(r),            —N(H)—C(O)—N(R^(r))—R^(r), —N(H)—C(S)—N(R^(r))—R^(r),            —N(R^(r))—C(O)—N(R^(r))—R^(r),            —N(R^(r))—C(S)—N(R^(r))—R^(r), —N(H)—S(O)₂—N(H)—R^(r),            —N(R^(r))—S(O)₂—NH₂, —N(R^(r))—S(O)₂—N(H)—R^(r),            —N(H)—S(O)₂—N(R^(r))—R^(r), —N(R^(r))—S(O)₂—N(R^(r))—R^(r),            —N(R^(r))—R^(r), cycloalkylamino, and —R^(x);        -   wherein each R^(r), R^(s), and R^(t) at each occurrence are            independently selected from the group consisting of lower            alkyl, C₃₋₆ alkenyl, C₃₋₆alkynyl, cycloalkyl,            heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl            is optionally substituted with one or more, for example 1,            2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the            group consisting of —R^(y), fluoro, —OH, —NH₂, lower alkoxy,            fluoro substituted lower alkoxy, lower alkylthio, fluoro            substituted lower alkylthio, mono-alkylamino, di-alkylamino,            and cycloalkylamino, and wherein C₃₋₆ alkenyl or C₃₋₆            alkynyl are optionally substituted with one or more, for            example 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents            selected from the group consisting of —R^(y), fluoro, lower            alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro            substituted lower alkoxy, lower alkylthio, fluoro            substituted lower alkylthio, mono-alkylamino, di-alkylamino,            and cycloalkylamino, and wherein cycloalkyl,            heterocycloalkyl, aryl, and heteroaryl are optionally            substituted with one or more, for example 1, 2, 3, 4 or 5,            also 1, 2, or 3 substituents selected from the group            consisting of halogen, —OH, —NH₂, —NO₂, —CN, lower alkyl,            fluoro substituted lower alkyl, lower alkoxy, fluoro            substituted lower alkoxy, lower alkylthio, fluoro            substituted lower alkylthio, mono-alkylamino, di-alkylamino,            and cycloalkylamino, or R^(s) and R^(t) combine with the            nitrogen to which they are attached to form a 5-7 membered            heterocycloalkyl or a 5 or 7 membered nitrogen containing            heteroaryl, wherein the 5-7 membered heterocycloalkyl or 5            or 7 membered nitrogen containing heteroaryl are optionally            substituted with one or more, for example 1, 2, 3, 4 or 5,            also 1, 2, or 3 substituents selected from the group            consisting of halogen, —NO₂, —CN, —OH, —NH₂, —O—R^(u),            —S—R^(u), —N(H)—R^(u), —N(R^(u))—R^(u), —R^(x), and —R^(y);        -   wherein each R^(u) is independently selected from the group            consisting of lower alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl,            cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein            lower alkyl is optionally substituted with one or more, for            example 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents            selected from the group consisting of —R^(y), fluoro, —OH,            —NH₂, lower alkoxy, fluoro substituted lower alkoxy, lower            alkylthio, fluoro substituted lower alkylthio,            mono-alkylamino, di-alkylamino, and cycloalkylamino, and            wherein C₃₋₆ alkenyl or C₃₋₆ alkynyl are optionally            substituted with one or more, for example 1, 2, 3, 4 or 5,            also 1, 2, or 3 substituents selected from the group            consisting of —R^(y), fluoro, —OH, —NH₂, lower alkyl, fluoro            substituted lower alkyl, lower alkoxy, fluoro substituted            lower alkoxy, lower alkylthio, fluoro substituted lower            alkylthio, mono-alkylamino, di-alkylamino, and            cycloalkylamino, and wherein cycloalkyl, heterocycloalkyl,            aryl, and heteroaryl are optionally substituted with one or            more, for example 1, 2, 3, 4 or 5, also 1, 2, or 3            substituents selected from the group consisting of halogen,            —OH, —NH₂, —NO₂, —CN, lower alkyl, fluoro substituted lower            alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower            alkylthio, fluoro substituted lower alkylthio,            mono-alkylamino, di-alkylamino, and cycloalkylamino;        -   wherein each R^(x) is selected from the group consisting of            lower alkyl, lower alkenyl and lower alkynyl, wherein lower            alkyl is optionally substituted with one or more, for            example 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents            selected from the group consisting of —R^(y), fluoro, —OH,            —NH₂, lower alkoxy, fluoro substituted lower alkoxy, lower            alkylthio, fluoro substituted lower alkylthio,            mono-alkylamino, di-alkylamino, and cycloalkylamino, and            wherein lower alkenyl or lower alkynyl are optionally            substituted with one or more, for example 1, 2, 3, 4 or 5,            also 1, 2, or 3 substituents selected from the group            consisting of —R^(y), fluoro, —OH, —NH₂, lower alkyl, fluoro            substituted lower alkyl, lower alkoxy, fluoro substituted            lower alkoxy, lower alkylthio, fluoro substituted lower            alkylthio, mono-alkylamino, di-alkylamino, and            cycloalkylamino;        -   wherein each R^(y) is selected from the group consisting of            cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein            cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are            optionally substituted with one or more, for example 1, 2,            3, 4 or 5, also 1, 2, or 3 substituents selected from the            group consisting of halogen, —OH, —NH₂, —NO₂, —CN, lower            alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro            substituted lower alkoxy, lower alkylthio, fluoro            substituted lower alkylthio, mono-alkylamino, di-alkylamino,            and cycloalkylamino.

In some embodiments, all occurrences of optionally substituted loweralkyl, optionally substituted lower alkenyl, optionally substituted C₃₋₆alkenyl, optionally substituted lower alkynyl, or optionally substitutedC₃₋₆ alkynyl are optionally substituted with one or more, also 1, 2 or 3groups or substituents selected from the group consisting of fluoro,—NO₂, —CN, —O—R^(1a), —S—R^(1a), —N(R^(1a))—R^(1a), —O—C(O)—R^(1a),—O—C(S)—R^(1a), —C(O)—R^(1a), —C(S)—R^(1a), —C(O)—O—R^(1a),—C(S)—O—R^(1a), —C(O)—N(R^(1a))—R^(1a), —C(S)—N(R^(1a))—R^(1a),—S(O)₂—N(R^(1a))—R^(1a), —C(NH)—N(R^(1a))—R^(1a),—N(R^(1a))—C(O)—R^(1a), —N(R^(1a))—C(S)—R^(1a), —N(R^(1a))—S(O)₂—R^(1a),—N(R^(1a))—C(O)—N(R^(1a))—R^(1a), —N(R^(1a))—C(S)—N(R^(1a))—R^(1a),—N(R^(1a))—S(O)₂—N(R^(1a))—R^(1a), —S(O)—R^(1a), —S(O)₂—R^(1a),cycloalkyl, heterocycloalkyl, aryl and heteroaryl; wherein cycloalkyl,heterocycloalkyl, aryl and heteroaryl are optionally substituted withone or more, also 1, 2 or 3 groups or substituents selected from thegroup consisting of halogen, —NO₂, —CN, —O—R^(1a), —S—R^(1a),—N(R^(1a))—R^(1a), —O—C(O)—R^(1a), —O—C(S)—R^(1a), —C(O)—R^(1a),—C(S)—R^(1a), —C(O)—O—R^(1a), —C(S)—O—R^(1a), —C(O)—N(R^(1a))—R^(1a),—C(S)—N(R^(1a))—R^(1a), —S(O)₂—N(R^(1a))—R^(1a),—C(NH)—N(R^(1a))—R^(1a), —N(R^(1a))—C(O)—R^(1a), —N(R^(1a))—C(S)—R^(1a),—N(R^(1a))—S(O)₂—R^(1a), —N(R^(1a))—C(O)—N(R^(1a))—R^(1a),—N(R^(1a))—C(S)—N(R^(1a))—R^(1a), —N(R^(1a)) S(O)₂—N(R^(1a))—R^(1a),S(O) R^(1a), —S(O)₂—R^(1a), —R^(1b), and lower alkyl optionallysubstituted with one or more, also 1, 2 or 3 groups or substituentsselected from the group consisting of fluoro, —OH, —NH₂, lower alkoxy,fluoro substituted lower alkoxy, lower alkylthio, fluoro substitutedlower alkylthio, mono-alkylamino, di-alkylamino, and —R^(1b); and alloccurrences of optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted 5-7 membered heterocycloalkyl,optionally substituted aryl, optionally substituted heteroaryl, oroptionally substituted 5 or 7 membered nitrogen containing heteroarylare optionally substituted with one or more, also 1, 2, or 3 groups orsubstituents selected from the group consisting of halogen, —NO₂, —CN,—O—R^(1a), —S—R^(1a), —N(R^(1a))—R^(1a), —O—C(O)—R^(1a), —O—C(S)—R^(1a),—C(O)—R^(1a), —C(S)—R^(1a), —C(O)—O—R^(1a), —C(S)—O—R^(1a),—C(O)—N(R^(1a))—R^(1a), —C(S)—N(R^(1a))—R^(1a), S(O)₂—N(R^(1a)) R^(1a),—C(NH)—N(R^(1a))—R^(1a), —N(R^(1a))—C(O)—R^(1a), —N(R^(1a))—C(S)—R^(1a),—N(R^(1a))—S(O)₂—R^(1a), —N(R^(1a))—C(O)—N(R^(1a))—R^(1a),—N(R^(1a))—C(S)—N(R^(1a))—R^(1a), —N(R^(1a))—S(O)₂—N(R^(1a))—R^(1a),—S(O)—R^(1a), —S(O)₂—R^(1a), —R^(1b), and lower alkyl optionallysubstituted with one or more, also 1, 2 or 3 groups or substituentsselected from the group consisting of fluoro, —OH, —NH₂, lower alkoxy,fluoro substituted lower alkoxy, lower alkylthio, fluoro substitutedlower alkylthio, mono-alkylamino, di-alkylamino, and —R^(1b); whereinR^(1a) is selected from the group consisting of hydrogen, —R^(1b), andlower alkyl optionally substituted with one or more, also 1, 2 or 3groups or substituents selected from the group consisting of fluoro,—OH, —NH₂, lower alkoxy, fluoro substituted lower alkoxy, loweralkylthio, fluoro substituted lower alkylthio, mono-alkylamino,di-alkylamino, and R^(1b), and wherein R^(1b) is selected from the groupconsisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl, whereincycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionallysubstituted with one or more, also 1, 2 or 3 groups or substituentsselected from the group consisting of halogen, —CN, —OH, —NH₂, loweralkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluorosubstituted lower alkylthio, mono-alkylamino, di-alkylamino, andcycloalkylamino.

In some embodiments, all occurrences of optionally substituted loweralkyl, optionally substituted lower alkenyl, optionally substituted C₃₋₆alkenyl, optionally substituted lower alkynyl, or optionally substitutedC₃₋₆ alkynyl are optionally substituted with one or more, also 1, 2 or 3groups or substituents selected from the group consisting of fluoro,—CN, —O—R^(1a), —S—R^(1a), —N(R^(1a))—R^(1a), —C(O)—R^(1a),—C(S)—R^(1a), —C(O)—O—R^(1a), —C(O)—N(R^(1a))—R^(1a),—C(S)—N(R^(1a))—R^(1a), —S(O)₂—N(R^(1a))—R^(1a), —N(R^(1a))—C(O)—R^(1a),—N(R^(1a))—C(S)—R^(1a), —N(R^(1a))—S(O)₂—R^(1a), —S(O)—R^(1a),—S(O)₂—R^(1a), cycloalkyl, heterocycloalkyl, aryl and heteroaryl,wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionallysubstituted with one or more, also 1, 2 or 3 groups or substituentsselected from the group consisting of halogen, —CN, —O—R^(1a),—S—R^(1a), —N(R^(1a))—R^(1a), —C(O)—R^(1a), —C(S)—R^(1a),—C(O)—O—R^(1a), —C(O)—N(R^(1a))—R^(1a), —C(S)—N(R^(1a))—R^(1a),—S(O)₂—N(R^(1a))—R^(1a), —N(R^(1a))—C(O)—R^(1a), —N(R^(1a))—C(S)—R^(1a),—N(R^(1a))—S(O)₂—R^(1a), —S(O)—R^(1a), —S(O)₂—R^(1a), —R^(1b), and loweralkyl optionally substituted with one or more, also 1, 2 or 3 groups orsubstituents selected from the group consisting of fluoro, —OH, —NH₂,lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluorosubstituted lower alkylthio, mono-alkylamino, di-alkylamino, and—R^(1b); and all occurrences of optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted 5-7membered heterocycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, or optionally substituted 5 or 7 memberednitrogen containing heteroaryl are optionally substituted with one ormore, also 1, 2, or 3 groups or substituents selected from the groupconsisting of halogen, —CN, —O—R^(1a), —S—R^(1a), —N(R^(1a))—R^(1a),—C(O)—R^(1a), —C(S)—R^(1a), —C(O)—O—R^(1a), —C(O)—N(R^(1a))—R^(1a),—C(S)—N(R^(1a))—R^(1a), —S(O)₂—N(R^(1a))—R^(1a), —N(R^(1a))—C(O)—R^(1a),—N(R^(1a))—C(S)—R^(1a), —N(R^(1a))—S(O)₂—R^(1a), —S(O)—R^(1a),—S(O)₂—R^(1a), —R^(1b), and lower alkyl optionally substituted with oneor more, also 1, 2 or 3 groups or substituents selected from the groupconsisting of fluoro, —OH, —NH₂, lower alkoxy, fluoro substituted loweralkoxy, lower alkylthio, fluoro substituted lower alkylthio,mono-alkylamino, di-alkylamino, and —R^(1b); wherein R^(1a) is selectedfrom the group consisting of hydrogen, —R^(1b), and lower alkyloptionally substituted with one or more, also 1, 2 or 3 groups orsubstituents selected from the group consisting of fluoro, —OH, —NH₂,lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluorosubstituted lower alkylthio, mono-alkylamino, di-alkylamino, and—R^(1b), and wherein —R^(1b) is selected from the group consisting ofcycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl and heteroaryl are optionally substituted withone or more, also 1, 2 or 3 groups or substituents selected from thegroup consisting of halogen, —CN, —OH, —NH₂, lower alkoxy, fluorosubstituted lower alkoxy, lower alkylthio, fluoro substituted loweralkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino.

As used herein, “lower alkoxy” denotes the group —OR^(z), where R^(z) islower alkyl. “Substituted lower alkoxy” denotes lower alkoxy in whichR^(z) is lower alkyl substituted with one or more substituents asindicated herein, for example, in the description of compounds ofFormula I, including descriptions of substituted cycloalkyl,heterocycloalkyl, aryl and heteroaryl, attached at any available atom toprovide a stable compound. In some embodiments, substitution of loweralkoxy is with 1, 2, 3, 4, or 5 substituents, also 1, 2, or 3substituents. For example, “fluoro substituted lower alkoxy” denoteslower alkoxy in which the lower alkyl is substituted with one or morefluoro atoms, where in some embodiments, the lower alkoxy is substitutedwith 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. It isunderstood that substitutions on alkoxy are chemically feasible andattached at any available atom to provide a stable compound.

It is understood that all possible substitutions as defined aboveinclude subsets of these substitutions, such as are indicated herein,for example, in the description of compounds of Formula I, attached atany available atom to produce a stable compound. For example, “fluorosubstituted phenyl” denotes a phenyl group substituted with one or morefluoro atoms where, for example, the phenyl is substituted with 1, 2, 3,4 or 5 fluoro atoms, e.g., 2,3,5,6-tetrafluorophenyl. It also isunderstood that any of the substitutions made according to thedefinitions above are chemically feasible and attached at any availableatom to provide a stable compound.

It is to be understood that the compounds provided herein can containchiral centers. Such chiral centers can be of either the (R) or (S)configuration, or can be a mixture thereof. Thus, the compounds providedherein can be enantiomerically pure, or be stereoisomeric ordiastereomeric mixtures. As such, one of skill in the art will recognizethat administration of a compound in its (R) form is equivalent, forcompounds that undergo epimerization in vivo, to administration of thecompound in its (S) form.

As used herein, “substantially pure” means sufficiently homogeneous toappear free of readily detectable impurities as determined by standardmethods of analysis, such as thin layer chromatography (TLC), gelelectrophoresis, high performance liquid chromatography (HPLC) and massspectrometry (MS), used by those of skill in the art to assess suchpurity, or sufficiently pure such that further purification would notdetectably alter the physical and chemical properties, such as enzymaticand biological activities, of the substance. Methods for purification ofthe compounds to produce substantially chemically pure compounds areknown to those of skill in the art. A substantially chemically purecompound may, however, be a mixture of stereoisomers. In such instances,further purification might increase the specific activity of thecompound. The instant disclosure is meant to include all such possibleisomers, as well as, their racemic and optically pure forms. Opticallyactive (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers can beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques, such as reverse phase HPLC. When the compoundsdescribed herein contain olefinic double bonds or other centers ofgeometric asymmetry, and unless specified otherwise, it is intended thatthe compounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

In certain embodiments, the compound used in the methods provided hereinis “stereochemically pure.” A stereochemically pure compound or has alevel of stereochemical purity that would be recognized as “pure” bythose of skill in the art. In certain embodiments, “stereochemicallypure” designates a compound that is substantially free of alternateisomers. In particular embodiments, the compound is 85%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% free of other isomers.

The singular forms “a,” “an,” and “the” include plural references,unless the context clearly dictates otherwise.

As used herein “subject” is an animal, such as a mammal, includinghuman, such as a patient.

As used herein, “biological activity” refers to the in vitro or in vivoactivities of a compound, or physiological responses that result upon invivo administration of a compound, composition or other mixture.Biological activity, thus, encompasses therapeutic effects andpharmacokinetic behavior of such compounds, compositions and mixtures.Biological activities can be observed in in vitro and in vitro systemsdesigned to test for such activities.

As used herein, “pharmaceutically acceptable derivatives” of a compoundinclude salts, esters, acetals, ketals, orthoesters, hemiacetals,hemiketals, acids, bases, solvates, hydrates or prodrugs thereof. Suchderivatives can readily be prepared by those of skill in this art usingknown methods for such derivatization. The compounds produced can beadministered to animals or humans without substantial toxic effects andeither are pharmaceutically active or are prodrugs. Pharmaceuticallyacceptable salts include, but are not limited to, amine salts, such asbut not limited to N,N′-dibenzylethylenediamine, chloroprocaine,choline, ammonia, diethanolamine and other hydroxyalkylamines,ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine,1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethylbenzimidazole, diethylamineand other alkylamines, piperazine and tris(hydroxymethyl)aminomethane;alkali metal salts, such as but not limited to lithium, potassium andsodium; alkali earth metal salts, such as but not limited to barium,calcium and magnesium; transition metal salts, such as but not limitedto zinc; and inorganic salts, such as but not limited to, sodiumhydrogen phosphate and disodium phosphate; and also including, but notlimited to, salts of mineral acids, such as but not limited tohydrochlorides and sulfates; and salts of organic acids, such as but notlimited to acetates, lactates, malates, tartrates, citrates, ascorbates,succinates, butyrates, valerates, mesylates, and fumarates.Pharmaceutically acceptable esters include, but are not limited to,alkyl, alkenyl, alkynyl, aryl, arylalkyl, and cycloalkyl esters ofacidic groups, including, but not limited to, carboxylic acids,phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids andboronic acids. Pharmaceutically acceptable solvates and hydrates arecomplexes of a compound with one or more solvent or water molecules, or1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent orwater molecules. Exemplary prodrugs include those set forth in Rautio J,Meanwell N A, di L, Hageman M J. The expanding role of prodrugs incontemporary drug design and development. Nat Rev Drug Discov. 2018;17(8):559-587, which is incorporated by reference in its entirety

As used herein, “treatment” means any manner in which a disease ordisorder, or one or more of the symptoms of a disease or disorder, areameliorated or otherwise beneficially altered. Treatment alsoencompasses any pharmaceutical use of the compositions herein, such asuse for treating cancer. Reference to “treatment,” herein also includesprevention, amelioration or mitigation.

As used herein, “prevention” means any manner in which the risk ofcontracting a disease or disorder, or of experiencing one or more of thesymptoms of a disease or disorder, is reduced. Such risk can be reducedby, for example, between about 5% to 100%, such as by about 5, 10, 15,20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100%.

As used herein, “amelioration” or “mitigation” of the symptoms of aparticular disorder by administration of a particular compound orpharmaceutical composition are used interchangeably and refers to anylessening of the symptoms, whether permanent or temporary, lasting ortransient that can be attributed to or associated with administration ofthe compound or composition.

As used herein, “complication” refers to a condition that develops inassociation with a condition or disease. The complication can be as adirect result caused by the condition or disease, or can be associatedwith the existence of the primary condition or disease. In someembodiments, the complications of a disease can be manifested as asymptom and, in those instances, the two terms are used interchangeablyherein.

As used herein, and unless otherwise indicated, the terms “manage,”“managing” and “management” encompass preventing the recurrence of thespecified disease or disorder in a patient who has already suffered fromthe disease or disorder, and/or lengthening the time that a patient whohas suffered from the disease or disorder remains in remission. Theterms encompass modulating the threshold, development and/or duration ofthe disease or disorder, or changing the way that a patient responds tothe disease or disorder.

As used herein, the term “in combination” refers to the use of more thanone therapies (e.g., a caspase inhibitor and other agents). The use ofthe term “in combination” does not restrict the order in which therapies(e.g., a caspase inhibitor and other agents) are administered to asubject with a disorder. A first therapy (e.g., a caspase inhibitor andother agents) can be administered prior to (e.g., 5 minutes, 15 minutes,30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks,5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, orsubsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours,96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks,or 12 weeks after) the administration of other therapy (e.g., a caspaseinhibitor and other agents) to a subject with a disorder.

The term “parenteral” as used herein includes administration of acompound to a subject using subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal,intralesional and intracranial injection or infusion techniques.

As used herein, “selective inhibitor of caspase-1, caspase-4, and/orcaspase-5” means the compounds provided herein binds to caspase-1,caspase-4, and/or caspase-5 more selectively than to caspase-3, caspase6, and/or caspase 7. In certain embodiments, the compounds providedherein have at least 2-fold higher binding affinity for caspase-1 ascompared to other caspases. In certain embodiments, the compoundsprovided herein have at least 5-fold, 10-fold, 50-fold, 100-fold,1000-fold or higher binding affinity for caspase-1, caspase-4, and/orcaspase-5 as compared to caspase-3, caspase 6, and/or caspase 7.

The term “about,” as used herein, unless otherwise indicated, refers toa value that is no more than 10% above or below the value being modifiedby the term. For example, the term “about 10 mg” means a range of from 9mg to 11 mg.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC IUBCommission on Biochemical Nomenclature (see, Biochem. 1972, 11:942 944).

6.2. Caspase Inhibitor Compounds

In one embodiment, provided herein is a compound of Formula I:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof;

wherein

X and Y are selected as follows:

i) X is C═O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,—R^(a)OR^(b), or —R^(a)N(R^(c))(R^(d)), each of which is optionallysubstituted; or

ii) X is —O—, or —N(R^(c))—; Y is hydrogen, —C(O)R^(d), optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl;

R³, Y¹, Y² and Y³ are selected as follows:

i) Y¹ together with R³ forms an optionally substituted saturated orunsaturated bicyclic ring B;

Y² is absent, hydrogen or optionally substituted alkyl; and

Y³ is absent, hydrogen or optionally substituted alkyl; or

ii) R³ is hydrogen or optionally substituted alkyl; Y¹ and Y² togetherare ═O; and Y³ is —N(Z¹)(Z²);

X, Y, R³ and Y¹ are selected such that when X is O, then Y¹ and R³cannot form ring B;

each R^(a) is independently alkylene or a direct bond;

R^(b) is hydrogen, optionally substituted alkyl, optionally substitutedhaloalkyl, optionally substituted hydroxyalkyl, optionally substitutedalkoxyalkyl, optionally substituted cycloalkyl, optionally substitutedaryl, optionally substituted heteroaryl or optionally substitutedheterocyclyl;

each R^(c) is independently hydrogen or optionally substituted alkyl;

each R^(d) is independently alkyl, aryl, cycloalkyl, heteroaryl,heterocyclyl or —R^(a)OR^(b), each of which is optionally substituted;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen, optionally substitutedalkyl or optionally substituted cycloalkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form an optionally substituted saturated or unsaturated ringA;

R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently hydrogen or optionallysubstituted alkyl;

R⁹ is aryl or heteroaryl, each optionally substituted;

R¹⁰ is alkylene;

Z¹ and Z² are selected as follows:

i) Z¹ is hydrogen or optionally substituted alkyl; and Z² is aryl,cycloalkyl, heteroaryl or heterocyclyl, each optionally substituted; or

ii) Z¹ and Z² together with the nitrogen atom on which they aresubstituted form an optionally substituted saturated or unsaturated ringC.

In one embodiment, provided herein is a compound of Formula I or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof;

wherein

X and Y are selected as follows:

i) X is C═O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,—R^(a)OR^(b), or —R^(a)N(R^(c))(R^(d)); or

ii) X is —O—, or —N(R^(c))—; Y is hydrogen, —C(O)R^(d), alkyl,cycloalkyl, heterocyclyl, aryl, heteroaryl;

Y is optionally substituted with one to three groups Q¹;

R³, Y¹, Y² and Y³ are selected as follows:

i) Y¹ together with R³ forms an optionally substituted saturated orunsaturated bicyclic ring B, where substituents on ring B, when present,are selected from one to three groups Q¹;

Y² is absent, hydrogen or alkyl; and

Y³ is absent, hydrogen or alkyl; or

ii) R³ is hydrogen or alkyl; Y¹ and Y² together are ═O; and Y³ is—N(Z¹)(Z²);

X, Y, R³ and Y¹ are selected such that when X is O, then Y¹ and R³cannot form ring B;

each Q¹ is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy,cycloalkyl, heterocyclyl, aryl or heteroaryl; each Q¹ is optionallysubstituted with one to three groups Q²; each Q² is independently alkyl,halo, haloalkyl, aryl or haloaryl;

each R^(a) is independently alkylene or a direct bond;

R^(b) is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl;

each R^(c) is independently hydrogen or alkyl;

each R^(d) is independently alkyl, aryl, cycloalkyl, heteroaryl,heterocyclyl or —R^(a)OR^(b);

each R^(d) is optionally substituted with one to three groups Q¹;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen, alkyl or cycloalkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form an optionally substituted saturated or unsaturated ringA, where the substituents on ring A, when present, are selected from oneto three groups Q¹;

R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently hydrogen or alkyl;

R⁹ is aryl or heteroaryl, each optionally substituted with one to foursubstituents Q¹;

R¹⁰ is alkylene;

Z¹ and Z² are selected as follows:

i) Z¹ is hydrogen or alkyl; and Z² is aryl, cycloalkyl, heteroaryl orheterocyclyl, each optionally substituted with one to four substituentsQ³; or

ii) Z¹ and Z² together with the nitrogen atom on which they aresubstituted form an optionally substituted saturated or unsaturated ringC, where the substituents on ring C, when present, are selected from oneto three groups Q³;

each Q³ is independently selected from alkyl, halo, cyano, cycloalkyl,heterocyclyl, aryl, heteroaryl, —R¹¹OR¹², —R¹¹OR¹¹OR¹², —R¹¹N(R¹³)(R¹⁴),—R¹¹SR¹², —R¹¹OR¹¹N(R¹³)(R¹⁴), —R¹¹C(J)N(R¹³)(R¹⁴),—R¹¹OR¹¹C(J)N(R¹³)(R¹⁴), —C(J)R¹⁵ and R¹¹S(O)_(t)R¹⁶; where each Q³ isoptionally substituted with one to three groups Q⁴, where each Q⁴ isindependently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl;

each R¹¹ is independently alkylene, alkenylene or a direct bond;

each R¹² is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

R¹³ and R¹⁴ are selected as follows:

i) R¹³ and R¹⁴ are each independently hydrogen, alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;or

ii) R¹³ and R¹⁴ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two alkyl, halo, haloalkyl, hydroxyl,alkoxy or cycloalkyl;

each R¹⁵ is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl,aryl, heteroaryl, heterocyclyl or heterocyclyl;

each R¹⁶ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

J is O or S; and

t is 0-2.

In one embodiment, provided herein is a compound of Formula I, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein

X and Y are selected as follows:

i) X is C═O; and Y is —R^(a)OR^(b); or

ii) X is —O—; Y is hydrogen, —C(O)R^(d), alkyl or aryl;

Y is optionally substituted with one to three groups Q¹;

R³, Y¹, Y² and Y³ are selected as follows:

i) Y¹ together with R³ forms an optionally substituted saturated orunsaturated ring B, where substituents on ring B, when present, areselected from one to three groups Q³;

Y² is absent, hydrogen or alkyl; and

Y³ is absent, hydrogen or alkyl; or

ii) R³ is hydrogen or alkyl; Y¹ and Y² together are ═O; and Y³ is—N(Z¹)(Z²); X, Y, R³ and Y¹ are selected such that when X is O, then Y¹and R³ cannot form ring B;

each Q¹ is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy,cycloalkyl, heterocyclyl, aryl or heteroaryl; each Q¹ is optionallysubstituted with one to three groups Q²; each Q² is independently alkyl,halo, haloalkyl, aryl or haloaryl;

R^(a) is alkylene or a direct bond;

R^(b) is hydrogen, alkyl or aryl;

R^(d) is aryl or —R^(a)OR^(b);

each R^(d) is optionally substituted with one to three groups Q¹;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen or alkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form a cycloalkyl ring;

R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently hydrogen or alkyl;

R⁹ is aryl or heteroaryl, each optionally substituted with one to foursubstituents Q¹;

R¹⁰ is alkylene;

Z¹ is hydrogen or alkyl;

Z² is aryl or heteroaryl, each optionally substituted with one to foursubstituents Q³;

each Q³ is independently selected from alkyl, haloalkyl, haloalkoxy,halo, cyano, aryl, heteroaryl, —R¹¹OR¹², —C(O)R¹⁵ and —R¹¹C(O)NH₂;

each R¹¹ is independently alkylene or a direct bond;

R¹² is hydrogen, alkyl or haloalkyl; and

R¹⁵ is hydroxyl or alkyl.

In one embodiment, provided herein is a compound of Formula I, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein

X and Y are selected as follows:

i) X is C═O; and Y is —R^(a)OR^(b); or

ii) X is —O—; Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or—C(O)R^(d); where the alkyl and aryl groups are optionally substitutedwith one or two groups selected from alkyl and halo;

R³, Y¹, Y² and Y³ are selected as follows:

i) Y¹ together with R³ forms an optionally substituted saturated orunsaturated ring B, where substituents on ring B, when present, areselected from one to three groups Q³;

Y² is absent, hydrogen or alkyl; and

Y³ is absent, hydrogen or alkyl; or

ii) R³ is hydrogen or alkyl; Y¹ and Y² together are ═O; and Y³ is—N(Z¹)(Z²);

X, Y, R³ and Y¹ are selected such that when X is O, then Y¹ and R³cannot form ring B;

R^(a) is alkylene or a direct bond;

R^(b) is hydrogen, alkyl or aryl;

R^(d) is aryl or aryloxy;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen or alkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form a cycloalkyl ring;

R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently hydrogen or alkyl;

R⁹ is aryl or heteroaryl, each optionally substituted with one to foursubstituents selected from halo, alkyl and haloalkyl;

R¹⁰ is alkylene;

Z¹ is hydrogen or alkyl;

Z² is aryl or heteroaryl, each optionally substituted with one to foursubstituents Q³;

each Q³ is independently selected from alkyl, haloalkyl, haloalkoxy,halo, cyano, aryl, heteroaryl, —R¹¹OR¹², —C(O)R¹⁵ and —C(O)NH₂;

R¹¹ is alkylene or a direct bond;

R¹² is hydrogen, alkyl or haloalkyl; and

R¹⁵ is hydroxyl or alkyl.

In one embodiment, provided herein is a compound of Formula II:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof;

wherein

X and Y are selected as follows:

i) X is C═O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,—R^(a)OR^(b), or —R^(a)N(R^(c))(R^(d)); or

ii) X is —O—, or —N(R^(c))—; Y is hydrogen, —C(O)R^(d), alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl;

Y is optionally substituted with one to three groups Q¹;

each Q¹ is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy,cycloalkyl, heterocyclyl, aryl or heteroaryl; each Q¹ is optionallysubstituted with one to three groups Q²; each Q² is independently alkyl,halo, haloalkyl, aryl or haloaryl;

each R^(a) is independently alkylene or a direct bond;

R^(b) is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl;

each R^(c) is independently hydrogen or alkyl;

each R^(d) is independently alkyl, aryl, cycloalkyl, heteroaryl,heterocyclyl or —R^(a)OR^(b);

each R^(d) is optionally substituted with one to three groups Q¹;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen, alkyl or cycloalkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form an optionally substituted saturated or unsaturated ringA, where substituents on ring A, when present, are selected from one tothree groups Q¹;

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently hydrogen or alkyl;

R⁹ is aryl or heteroaryl, each optionally substituted with one to foursubstituents Q¹;

R¹⁰ is alkylene;

Z¹ and Z² are selected as follows:

i) Z¹ is hydrogen or alkyl; and Z² is aryl, cycloalkyl, heteroaryl orheterocyclyl, each optionally substituted with one to four substituentsQ³; or

ii) Z¹ and Z² together with the nitrogen atom on which they aresubstituted form an optionally substituted saturated or unsaturated ringC, where the substituents on ring C, when present, are selected from oneto three groups Q³;

each Q³ is independently selected from alkyl, halo, cyano, cycloalkyl,heterocyclyl, aryl, heteroaryl, —R¹¹OR¹², —R¹¹OR¹¹OR¹², —R¹¹N(R¹³)(R¹⁴),—R¹¹SR¹², —R¹¹OR¹¹N(R¹³)(R¹⁴), —R¹¹C(J)N(R¹³)(R¹⁴),—R¹¹OR¹¹C(J)N(R¹³)(R¹⁴), —C(J)R¹⁵ and R¹¹S(O)_(t)R¹⁶; where each Q³ isoptionally substituted with one to three groups Q⁴, where each Q⁴ isindependently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl;

each R¹¹ is independently alkylene, alkenylene or a direct bond;

each R¹² is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

R¹³ and R¹⁴ are selected as follows:

i) R¹³ and R¹⁴ are each independently hydrogen, alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;or

ii) R¹³ and R¹⁴ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two alkyl, halo, haloalkyl, hydroxyl,alkoxy or cycloalkyl;

each R¹⁵ is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl,aryl, heteroaryl, heterocyclyl or heterocyclyl;

each R¹⁶ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

J is O or S; and

t is 0-2.

In one embodiment, provided herein is a compound of Formula II or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof;

wherein

X and Y are selected as follows:

i) X is C═O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,—R^(a)OR^(b), or —R^(a)N(R^(c))(R^(d)); or

ii) X is —O—, or —N(R^(c))—; Y is hydrogen, —C(O)R^(d), alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl;

Y is optionally substituted with one to three groups Q¹;

each Q¹ is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy,cycloalkyl, heterocyclyl, aryl, heteroaryl; each Q¹ is optionallysubstituted with one to three groups Q²; each Q² is independently alkyl,halo, haloalkyl, aryl or haloaryl;

each R^(a) is independently alkylene or a direct bond;

R^(b) is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl;

each R^(c) is independently hydrogen or alkyl;

each R^(d) is independently alkyl, aryl, cycloalkyl, heteroaryl,heterocyclyl or —R^(a)OR^(b);

each R^(d) is optionally substituted with one to three groups Q¹;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen, alkyl or cycloalkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form an optionally substituted saturated or unsaturated ringA, where substituents on ring A, when present, are selected from one tothree groups Q¹;

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently hydrogen or alkyl;

R⁹ is aryl or heteroaryl, each optionally substituted with one to foursubstituents Q¹;

R¹⁰ is alkylene;

Z¹ is hydrogen or alkyl;

Z² is aryl, cycloalkyl, heteroaryl or heterocyclyl, each optionallysubstituted with one to four substituents Q³;

each Q³ is independently selected from alkyl, halo, cyano, cycloalkyl,heterocyclyl, aryl, heteroaryl, —R¹¹OR¹², —R¹¹OR¹¹OR¹², —R¹¹N(R¹³)(R¹⁴),—R¹¹SR¹², —R¹¹OR¹¹N(R¹³)(R¹⁴), —R¹¹C(J)N(R¹³)(R¹⁴),—R¹¹OR¹¹C(J)N(R¹³)(R¹⁴), —C(J)R¹⁵ and R¹¹S(O)_(t)R¹⁶; where each Q³ isoptionally substituted with one to three groups Q⁴, where each Q⁴ isindependently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl;

each R¹¹ is independently alkylene, alkenylene or a direct bond;

each R¹² is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

R¹³ and R¹⁴ are selected as follows:

i) R¹³ and R¹⁴ are each independently hydrogen, alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;or

ii) R¹³ and R¹⁴ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two alkyl, halo, haloalkyl, hydroxyl,alkoxy or cycloalkyl;

each R¹⁵ is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl,aryl, heteroaryl, heterocyclyl or heterocyclyl;

each R¹⁶ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

J is O or S; and

t is 0-2.

In one embodiment, provided herein is a compound of Formula II, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein

X and Y are selected as follows:

i) X is C═O; and Y is —R^(a)OR^(b); or

ii) X is —O—; Y is hydrogen, —C(O)R^(d), alkyl or aryl;

Y is optionally substituted with one to three groups Q¹;

each Q¹ is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy,cycloalkyl, heterocyclyl, aryl or heteroaryl; each Q¹ is optionallysubstituted with one to three groups Q²;

each Q² is independently alkyl, halo, haloalkyl, aryl or haloaryl;

each R^(a) is independently alkylene or a direct bond;

each R^(b) is independently hydrogen, alkyl or aryl;

R^(d) is aryl or —R^(a)OR^(b);

each R^(d) is optionally substituted with one to three groups Q¹;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen or alkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form a cycloalkyl ring;

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently hydrogen or alkyl;

R⁹ is aryl or heteroaryl, each optionally substituted with one to foursubstituents Q¹;

R¹⁰ is alkylene;

Z¹ is hydrogen or alkyl;

Z² is aryl or heteroaryl, each optionally substituted with one to foursubstituents Q³;

each Q³ is independently selected from alkyl, haloalkyl, haloalkoxy,halo, cyano, aryl, heteroaryl, —R¹¹OR¹², —C(O)R¹⁵ and —R¹¹C(O)NH₂;

each R¹¹ is independently alkylene or a direct bond;

R¹² is hydrogen, alkyl or haloalkyl; and

R¹⁵ is hydroxyl or alkyl.

In one embodiment, provided herein is a compound of Formula II, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein

X and Y are selected as follows:

i) X is C═O; and Y is —R^(a)OR^(b); or

ii) X is —O—; Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or—C(O)R^(d); where the alkyl and aryl groups are optionally substitutedwith one or two groups selected from alkyl and halo;

R^(a) is alkylene or a direct bond;

R^(b) is hydrogen, alkyl or aryl;

R^(d) is aryl or aryloxy;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen or alkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form a cycloalkyl ring;

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently hydrogen or alkyl;

R⁹ is aryl or heteroaryl, each optionally substituted with one to foursubstituents selected from halo, alkyl and haloalkyl;

R¹⁰ is alkylene;

Z¹ is hydrogen or alkyl;

Z² is aryl or heteroaryl, each optionally substituted with one to foursubstituents Q³;

each Q³ is independently selected from alkyl, haloalkyl, haloalkoxy,halo, cyano, aryl, heteroaryl, —R¹¹OR¹², —C(O)R¹⁵ and —C(O)NH₂;

each R¹¹ is independently alkylene or a direct bond;

R¹² is hydrogen, alkyl or haloalkyl; and

R¹⁵ is hydroxyl or alkyl.

In one embodiment, provided herein is a compound of Formula III

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof;

wherein

X and Y are selected as follows:

i) X is C═O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,—R^(a)OR^(b), or —R^(a)N(R^(c))(R^(d)); or

ii) X is —O—, or —N(R^(c))—; Y is hydrogen, —C(O)R^(d), alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl;

Y is optionally substituted with one to three groups Q¹;

each Q¹ is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy,cycloalkyl, heterocyclyl, aryl or heteroaryl; each Q¹ is optionallysubstituted with one to three groups Q²; each Q² is independently alkyl,halo, haloalkyl, aryl or haloaryl;

each R^(a) is independently alkylene or a direct bond;

R^(b) is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl;

each R^(c) is independently hydrogen or alkyl;

each R^(d) is independently alkyl, aryl, cycloalkyl, heteroaryl,heterocyclyl or —R^(a)OR^(b);

each R^(d) is optionally substituted with one to three groups Q¹;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen, alkyl or cycloalkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form an optionally substituted saturated or unsaturated ringA, where substituents on ring A, when present, are selected from one tothree groups Q¹;

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently hydrogen or alkyl;

R¹⁰ is alkylene;

each Q⁵ is independently alkyl, halo or haloalkyl;

Z¹ is hydrogen or alkyl;

Z² is aryl, cycloalkyl, heteroaryl or heterocyclyl, each optionallysubstituted with one to four substituents Q³;

each Q³ is independently selected from alkyl, halo, cyano, cycloalkyl,heterocyclyl, aryl, heteroaryl, —R¹¹OR¹², —R¹¹OR¹¹OR¹², —R¹¹N(R¹³)(R¹⁴),—R¹¹SR¹², —R¹¹OR¹¹N(R¹³)(R¹⁴), —R¹¹C(J)N(R¹³)(R¹⁴),—R¹¹OR¹¹C(J)N(R¹³)(R¹⁴), —C(J)R¹⁵ and R¹¹S(O)_(t)R¹⁶; where each Q³ isoptionally substituted with one to three groups Q⁴, where each Q⁴ isindependently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl;

each R¹¹ is independently alkylene, alkenylene or a direct bond;

each R¹² is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

R¹³ and R¹⁴ are selected as follows:

i) R¹³ and R¹⁴ are each independently hydrogen, alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;or

ii) R¹³ and R¹⁴ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two alkyl, halo, haloalkyl, hydroxyl,alkoxy or cycloalkyl;

each R¹⁵ is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl,aryl, heteroaryl, heterocyclyl or heterocyclyl;

each R¹⁶ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

J is O or S;

t is 0-2; and

m is 0-4.

In one embodiment, provided herein is a compound of Formula III, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein

X and Y are selected as follows:

i) X is C═O; and Y is —R^(a)OR^(b); or

ii) X is —O—; Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or—C(O)R^(d); where the alkyl and aryl groups are optionally substitutedwith one or two groups selected from alkyl and halo;

R^(a) is alkylene or a direct bond;

R^(b) is hydrogen, alkyl or aryl;

each R^(d) is independently aryl or aryloxy;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen or alkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form a cycloalkyl ring;

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently hydrogen or alkyl;

Q¹ is selected from halo, alkyl and haloalkyl;

m is 0-4;

R¹⁰ is alkylene;

Z¹ is hydrogen or alkyl;

Z² is aryl or heteroaryl, each optionally substituted with one to foursubstituents Q³;

each Q³ is independently selected from alkyl, haloalkyl, haloalkoxy,halo, cyano, aryl, heteroaryl, —R¹¹OR¹², —C(O)R¹⁵ and —C(O)NH₂;

R¹¹ is alkylene or a direct bond;

R¹² is hydrogen, alkyl or haloalkyl; and

R¹⁵ is hydroxyl or alkyl.

In one embodiment, provided herein is a compound of Formula III, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein

X and Y are selected as follows:

i) X is C═O; and Y is —R^(a)OR^(b); or

ii) X is —O—; Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or—C(O)R^(d); where the alkyl and aryl groups are optionally substitutedwith one or two groups selected from alkyl and halo;

R^(a) is alkylene or a direct bond;

R^(b) is hydrogen, alkyl or aryl;

R^(d) is aryl or aryloxy;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen or alkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form a cycloalkyl ring;

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are hydrogen;

Q¹ is selected from halo, alkyl and haloalkyl;

m is 0-4;

R¹⁰ is alkylene;

R³, Y¹, Y² and Y³ are selected as follows:

i) Y¹ together with R³ forms an optionally substituted saturated orunsaturated ring B, where substituents on ring B, when present, areselected from one to three groups Q¹;

Y² is absent, hydrogen or alkyl; and

Y³ is absent, hydrogen or alkyl; or

ii) R³ is hydrogen or alkyl; Y¹ and Y² together are ═O; and Y³ is—N(Z¹)(Z²);

Z¹ is hydrogen or alkyl;

Z² is aryl or heteroaryl, each optionally substituted with one to foursubstituents Q³;

each Q³ is independently selected from alkyl, haloalkyl, haloalkoxy,halo, cyano, aryl, heteroaryl, —R¹¹OR¹², —C(O)R¹⁵ and —C(O)NH₂;

R¹¹ is alkylene or a direct bond;

R¹² is hydrogen, alkyl or haloalkyl; and

R¹⁵ is hydroxyl or alkyl.

In one embodiment, provided herein is a compound of Formula IV

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein

X and Y are selected as follows:

i) X is C═O; and Y is —R^(a)OR^(b); or

ii) X is —O—; Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or—C(O)R^(d); where the alkyl and aryl groups are optionally substitutedwith one or two groups selected from alkyl and halo;

R^(a) is alkylene or a direct bond;

R^(b) is hydrogen, alkyl or aryl;

R^(d) is aryl or aryloxy;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen or alkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form a cycloalkyl ring;

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are hydrogen;

Q⁵ is selected from halo, alkyl and haloalkyl;

p is 0-3;

R¹⁰ is alkylene;

Z¹ is hydrogen or alkyl;

Z² is aryl or heteroaryl, each optionally substituted with one to foursubstituents Q³;

each Q³ is independently selected from alkyl, haloalkyl, haloalkoxy,halo, cyano, aryl, heteroaryl, —R¹¹OR¹², —C(O)R¹⁵ and —C(O)NH₂;

R¹¹ is alkylene or a direct bond;

R¹² is hydrogen, alkyl or haloalkyl; and

R¹⁵ is hydroxyl or alkyl.

In one embodiment, provided herein is a compound of Formula V:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof;

wherein

X and Y are selected as follows:

i) X is C═O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,—R^(a)OR^(b), or —R^(a)N(R^(c))(R^(d)); or

ii) X is —O—, or —N(R^(c))—; Y is hydrogen, —C(O)R^(d), alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl;

Y is optionally substituted with one to three groups Q¹;

each Q¹ is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy,cycloalkyl, heterocyclyl, aryl or heteroaryl; each Q¹ is optionallysubstituted with one to three groups Q²;

each Q² is independently alkyl, halo, haloalkyl, aryl or haloaryl;

each R^(a) is independently alkylene or a direct bond;

R^(b) is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl;

each R^(c) is independently hydrogen or alkyl;

each R^(d) is independently alkyl, aryl, cycloalkyl, heteroaryl,heterocyclyl or —R^(a)OR^(b);

each R^(d) is optionally substituted with one to three groups Q¹;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen, alkyl or cycloalkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form an optionally substituted saturated or unsaturated ringA, where the substituents on ring A, when present, are selected from oneto three groups Q¹;

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently hydrogen or alkyl;

R¹⁰ is alkylene;

each Q³ is independently selected from alkyl, halo, cyano, cycloalkyl,heterocyclyl, aryl, heteroaryl, —R¹¹OR¹², —R¹¹OR¹¹R¹², —R¹¹N(R¹³)(R¹⁴),—R¹¹SR¹², —R¹¹OR¹¹N(R¹³)(R¹⁴), —R¹¹C(J)N(R¹³)(R¹⁴),—R¹¹OR¹¹C(J)N(R¹³)(R¹⁴), —C(J)R¹⁵ and R¹¹S(O)_(t)R¹⁶; where each Q³ isoptionally substituted with one to three groups Q⁴, where each Q⁴ isindependently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl;

each R¹¹ is independently alkylene, alkenylene or a direct bond;

each R¹² is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

R¹³ and R¹⁴ are selected as follows:

i) R¹³ and R¹⁴ are each independently hydrogen, alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;or

ii) R¹³ and R¹⁴ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two alkyl, halo, haloalkyl, hydroxyl,alkoxy or cycloalkyl;

each R¹⁵ is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl,aryl, heteroaryl, heterocyclyl or heterocyclyl;

each R¹⁶ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

each Q⁵ is independently alkyl, halo or haloalkyl;

J is O or S;

t is 0-2;

m is 0-4; and

n is 0-3.

In one embodiment, provided herein is a compound of Formula V, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein

X and Y are selected as follows:

i) X is C═O; and Y is —R^(a)OR^(b); or

ii) X is —O—; Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or—C(O)R^(d); where the alkyl and aryl groups are optionally substitutedwith one or two groups selected from alkyl and halo;

R^(a) is alkylene or a direct bond;

R^(b) is hydrogen, alkyl or aryl;

R^(d) is aryl or aryloxy;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen or alkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form a cycloalkyl ring;

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently hydrogen or alkyl;

R¹⁰ is alkylene;

Z¹ is hydrogen or alkyl;

each Q³ is independently selected from alkyl, haloalkyl, haloalkoxy,halo, cyano, aryl, heteroaryl, —R¹¹OR¹², —C(O)R¹⁵ and —C(O)NH₂;

each R¹¹ is independently alkylene or a direct bond;

R¹² is hydrogen, alkyl or haloalkyl;

R¹⁵ is hydroxyl or alkyl;

each Q⁵ is independently alkyl, halo or haloalkyl;

m is 0-4; and

n is 0-2.

In one embodiment, provided herein is a compound of Formula VI:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof;

wherein

Y is hydrogen, —C(O)R^(d), alkyl, cycloalkyl, heterocyclyl, aryl orheteroaryl;

Y is optionally substituted with one to three groups Q¹;

each Q¹ is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy,cycloalkyl, heterocyclyl, aryl or heteroaryl; each Q¹ is optionallysubstituted with one to three groups Q²; each Q² is independently alkyl,halo, haloalkyl, aryl or haloaryl;

R^(d) is alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or—R^(a)OR^(b);

each R^(d) is optionally substituted with one to three groups Q¹;

R^(a) is alkylene or a direct bond;

R^(b) is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen, alkyl or cycloalkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form an optionally substituted saturated or unsaturated ringA, where the substituents on ring A, when present, are selected from oneto three groups Q¹;

R³, R⁴, R⁵ and R⁶ are each independently hydrogen or alkyl;

Z¹ is hydrogen or alkyl;

Z² is aryl, cycloalkyl, heteroaryl or heterocyclyl, each optionallysubstituted with one to four substituents Q³;

each Q³ is independently selected from alkyl, halo, cyano, cycloalkyl,heterocyclyl, aryl, heteroaryl, —R¹¹OR¹², —R¹¹OR¹¹OR¹², —R¹¹N(R¹³)(R¹⁴),—R¹¹SR¹², —R¹¹OR¹¹N(R¹³)(R¹⁴), —R¹¹C(J)N(R¹³)(R¹⁴),—R¹¹OR¹¹C(J)N(R¹³)(R¹⁴), —C(J)R¹⁵ and R¹¹S(O)_(t)R¹⁶; where each Q³ isoptionally substituted with one to three groups Q⁴, where each Q⁴ isindependently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl;

R¹⁰ is —CH₂— or —CH₂—CH₂—;

each R¹¹ is independently alkylene, alkenylene or a direct bond;

each R¹² is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

R¹³ and R¹⁴ are selected as follows:

i) R¹³ and R¹⁴ are each independently hydrogen, alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;or

ii) R¹³ and R¹⁴ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two alkyl, halo, haloalkyl, hydroxyl,alkoxy or cycloalkyl;

each R¹⁵ is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl,aryl, heteroaryl, heterocyclyl or heterocyclyl;

each R¹⁶ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

J is O or S;

each Q⁵ is independently alkyl, halo or haloalkyl;

t is 0-2; and

m is 0-4.

In one embodiment, provided herein is a compound of Formula VI, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkylor —C(O)R^(d); where the alkyl and aryl groups are optionallysubstituted with one or two groups selected from alkyl and halo;

R^(d) is aryl or aryloxy;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen or alkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form a cycloalkyl ring;

R³, R⁴, R⁵ and R⁶ are each independently hydrogen or alkyl;

Z¹ is hydrogen or alkyl;

Z² is aryl or heteroaryl, each optionally substituted with one to foursubstituents Q³;

each Q³ is independently selected from alkyl, haloalkyl, haloalkoxy,halo, cyano, aryl, heteroaryl, —R¹¹OR¹², —C(O)R¹⁵ or —C(O)NH₂;

each Q⁵ is independently alkyl, halo or haloalkyl;

R¹⁰ is —CH₂— or —CH₂—CH₂—;

R¹¹ is alkylene or a direct bond;

R¹² is hydrogen, alkyl or haloalkyl;

R¹⁵ is hydroxyl or alkyl; and

m is 0-4.

In one embodiment, provided herein is a compound of Formula VI, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein

Y is hydrogen, methyl, —C(O)R^(d); where methyl is optionallysubstituted with phenyl, chlorophenyl or thienyl;

R^(d) is phenyl or phenyloxy;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen or methyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form a cyclopentyl ring;

R³, R⁴, R⁵ and R⁶ are each independently hydrogen or methyl;

R¹⁰ is —CH₂— or —CH₂—CH₂—;

Q⁵ is fluoro, methyl or trifluoromethyl;

Z¹ is hydrogen;

Z² is selected from phenyl, pyridinyl, pyrimidyl, naphthyl, indazolyl,quinolinyl, isoquinolynyl and benzoisothiazolyl; each optionallysubstituted with one or two Q³ groups, and each Q³ is independentlyselected from chloro, fluoro, methyl, methoxy, trifluoromethoxy,—C(O)CH₃, cyano, —C(O)NH₂, benzyl and tetrazolyl; and

m is 0-4.

In one embodiment, provided herein is a compound of Formula VII:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof;

wherein

R^(d) is alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or—R^(a)OR^(b);

each R^(d) is optionally substituted with one to three groups Q¹;

each Q¹ is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy,cycloalkyl, heterocyclyl, aryl or heteroaryl; each Q¹ is optionallysubstituted with one to three groups Q²; each Q² is independently alkyl,halo, haloalkyl, aryl or haloaryl;

R^(a) is alkylene or a direct bond;

R^(b) is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen, alkyl or cycloalkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form an optionally substituted saturated or unsaturated ringA, where the substituents on ring A, when present, are selected from oneto three groups Q¹;

R³, R⁴, R⁵ and R⁶ are each independently hydrogen or alkyl;

Z¹ is hydrogen or alkyl;

Z² is aryl, cycloalkyl, heteroaryl or heterocyclyl, each optionallysubstituted with one to four substituents Q³; or

each Q³ is independently selected from alkyl, halo, cyano, cycloalkyl,heterocyclyl, aryl, heteroaryl, —R¹¹OR¹², —R¹¹OR¹¹OR¹², —R¹¹N(R¹³)(R¹⁴),—R¹¹SR¹², —R¹¹OR¹¹N(R¹³)(R¹⁴), —R¹¹C(J)N(R¹³)(R¹⁴),—R¹¹OR¹¹C(J)N(R¹³)(R¹⁴), —C(J)R¹⁵ and R¹¹S(O)_(t)R¹⁶; where each Q³ isoptionally substituted with one to three groups Q⁴, where each Q⁴ isindependently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl;

R¹⁰ is —CH₂— or —CH₂—CH₂—;

each R¹¹ is independently alkylene, alkenylene or a direct bond;

each R¹² is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

R¹³ and R¹⁴ are selected as follows:

i) R¹³ and R¹⁴ are each independently hydrogen, alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;or

ii) R¹³ and R¹⁴ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two alkyl, halo, haloalkyl, hydroxyl,alkoxy or cycloalkyl;

each R¹⁵ is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl,aryl, heteroaryl, heterocyclyl or heterocyclyl;

each R¹⁶ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

each Q⁵ is independently alkyl, halo or haloalkyl;

J is O or S;

t is 0-2; and

m is 0-4.

In one embodiment, provided herein is a compound of Formula VII, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein

R^(d) is aryl or aryloxy;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen or alkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form a cycloalkyl ring;

R³, R⁴, R⁵ and R⁶ are each independently hydrogen or alkyl;

Z¹ is hydrogen or alkyl;

Z² is aryl or heteroaryl, each optionally substituted with one to foursubstituents Q³;

each Q³ is independently selected from alkyl, haloalkyl, haloalkoxy,halo, cyano, aryl, heteroaryl, —R¹¹OR¹², —C(O)R¹⁵ and —C(O)NH₂;

R¹⁰ is —CH₂— or —CH₂—CH₂—;

R¹ is alkylene or a direct bond;

R¹² is hydrogen, alkyl or haloalkyl;

R¹⁵ is hydroxyl or alkyl;

Q⁵ is independently alkyl, halo or haloalkyl; and

m is 0-4.

In one embodiment, provided herein is a compound of Formula VII, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein

each R^(d) is independently phenyl or phenyloxy;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen or methyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form a cyclopentyl ring;

R³, R⁴, R⁵ and R⁶ are each independently hydrogen or methyl;

R¹⁰ is —CH₂— or —CH₂—CH₂—;

Q⁵ is fluoro, methyl or trifluoromethyl;

Z¹ is hydrogen;

Z² is selected from phenyl, pyridinyl, pyrimidyl, naphthyl, indazolyl,quinolinyl, isoquinolynyl and benzoisothiazolyl; each optionallysubstituted with one or two Q³ groups, and each Q³ is independentlyselected from chloro, fluoro, methyl, methoxy, trifluoromethoxy,—C(O)CH₃, cyano, —C(O)NH₂, benzyl and tetrazolyl; and

m is 0-4.

In one embodiment, provided herein is a compound of Formula VIII:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof;

wherein

R^(b) is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl;

R^(b) is optionally substituted with one to three groups Q¹;

each Q¹ is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy,cycloalkyl, heterocyclyl, aryl or heteroaryl; each Q¹ is optionallysubstituted with one to three groups Q²;

each Q² is independently alkyl, halo, haloalkyl, aryl or haloaryl;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen, alkyl or cycloalkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form an optionally substituted saturated or unsaturated ringA, where the substituents on ring A, when present, are selected from oneto three groups Q¹;

R³, R⁴, R⁵ and R⁶ are each independently hydrogen or alkyl;

Z¹ is hydrogen or alkyl;

Z² is aryl, cycloalkyl, heteroaryl or heterocyclyl, each optionallysubstituted with one to four substituents Q³;

each Q³ is independently selected from alkyl, halo, cyano, cycloalkyl,heterocyclyl, aryl, heteroaryl, —R¹¹OR¹², —R¹¹OR¹¹OR¹², —R¹¹N(R¹³)(R¹⁴),—R¹¹SR¹², —R¹¹OR¹¹N(R¹³)(R¹⁴), —R¹¹C(J)N(R¹³)(R¹⁴),—R¹¹OR¹¹C(J)N(R¹³)(R¹⁴), —C(J)R¹⁵ and R¹¹S(O)_(t)R¹⁶; where each Q³ isoptionally substituted with one to three groups Q⁴, where each Q⁴ isindependently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl;

R¹⁰ is —CH₂— or —CH₂—CH₂—;

each R¹¹ is independently alkylene, alkenylene or a direct bond;

each R¹² is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

R¹³ and R¹⁴ are selected as follows:

i) R¹³ and R¹⁴ are each independently hydrogen, alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;or

ii) R¹³ and R¹⁴ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two alkyl, halo, haloalkyl, hydroxyl,alkoxy or cycloalkyl;

each R¹⁵ is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl,aryl, heteroaryl, heterocyclyl or heterocyclyl;

each R¹⁶ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

Q⁵ is independently alkyl, halo or haloalkyl;

J is O or S;

m is 0-4;

t is 0-2.

In one embodiment, provided herein is a compound of Formula VIII or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof;

wherein

R^(b) is hydrogen;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen, alkyl or cycloalkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form an optionally substituted saturated or unsaturated ringA, where the substituents on ring A, when present, are selected from oneto three groups Q¹;

each Q¹ is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy,cycloalkyl, heterocyclyl, aryl or heteroaryl; each Q¹ is optionallysubstituted with one to three groups Q²;

each Q² is independently alkyl, halo, haloalkyl, aryl or haloaryl;

R³, R⁴, R⁵ and R⁶ are each independently hydrogen or alkyl;

Z¹ is hydrogen or alkyl;

Z² is aryl, cycloalkyl, heteroaryl or heterocyclyl, each optionallysubstituted with one to four substituents Q³;

each Q³ is independently selected from alkyl, halo, cyano, cycloalkyl,heterocyclyl, aryl, heteroaryl, —R¹¹OR¹², —R¹¹OR¹¹OR¹², —R¹¹N(R¹³)(R¹⁴),—R¹¹SR¹², —R¹¹OR¹¹N(R¹³)(R¹⁴), —R¹¹C(J)N(R¹³)(R¹⁴),—R¹¹OR¹¹C(J)N(R¹³)(R¹⁴), —C(J)R¹⁵ and R¹¹S(O)_(t)R¹⁶; where each Q³ isoptionally substituted with one to three groups Q⁴, where each Q⁴ isindependently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl;

R¹⁰ is —CH₂— or —CH₂—CH₂—;

each R¹¹ is independently alkylene, alkenylene or a direct bond;

each R¹² is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

R¹³ and R¹⁴ are selected as follows:

i) R¹³ and R¹⁴ are each independently hydrogen, alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;or

ii) R¹³ and R¹⁴ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two alkyl, halo, haloalkyl, hydroxyl,alkoxy or cycloalkyl;

each R¹⁵ is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl,aryl, heteroaryl, heterocyclyl or heterocyclyl;

each R¹⁶ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

Q⁵ is independently alkyl, halo or haloalkyl;

J is O or S;

m is 0-4; and

t is 0-2.

In one embodiment, provided herein is a compound of Formula VIII, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein

R^(b) is hydrogen, alkyl or aryl;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen or alkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form a cycloalkyl ring;

R³, R⁴, R⁵ and R⁶ are each independently hydrogen or alkyl;

Z¹ is hydrogen or alkyl;

Z² is aryl or heteroaryl, each optionally substituted with one to foursubstituents Q³;

each Q³ is independently selected from alkyl, haloalkyl, haloalkoxy,halo, cyano, aryl, heteroaryl, —R¹¹OR¹², —C(O)R¹⁵ and —C(O)NH₂;

R¹⁰ is —CH₂— or —CH₂—CH₂—;

R¹ is alkylene or a direct bond;

R¹² is hydrogen, alkyl or haloalkyl;

R¹⁵ is hydroxyl or alkyl;

Q⁵ is independently alkyl, halo or haloalkyl; and

m is 0-4.

In one embodiment, provided herein is a compound of Formula VIII, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein

R^(b) is hydrogen;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen or alkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form a 3-5 membered cycloalkyl ring;

R³, R⁴, R⁵ and R⁶ are each independently hydrogen or alkyl;

Z¹ is hydrogen or alkyl;

Z² is aryl or heteroaryl, each optionally substituted with one to foursubstituents Q³;

each Q³ is independently selected from alkyl, haloalkyl, haloalkoxy,halo, cyano, aryl, heteroaryl, —R¹¹OR¹², —C(O)R¹⁵ and —C(O)NH₂;

R¹⁰ is —CH₂— or —CH₂—CH₂—;

R¹¹ is alkylene or a direct bond;

R¹² is hydrogen, alkyl or haloalkyl;

R¹⁵ is hydroxyl or alkyl;

Q⁵ is independently alkyl, halo or haloalkyl; and

m is 0-4.

In one embodiment, provided herein is a compound of Formula VIII, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein

R^(b) is hydrogen;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen or methyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form a cyclopentyl ring;

R³, R⁴, R⁵ and R⁶ are each independently hydrogen or methyl;

R¹⁰ is —CH₂— or —CH₂—CH₂—;

Q⁵ is fluoro, methyl and trifluoromethyl;

Z¹ is hydrogen;

Z² is selected from phenyl, pyridinyl, pyrimidyl, naphthyl, indazolyl,quinolinyl, isoquinolynyl and benzoisothiazolyl; each optionallysubstituted with one or two Q³ groups, and each Q³ is independentlyselected from chloro, fluoro, methyl, methoxy, trifluoromethoxy,—C(O)CH₃, cyano, —C(O)NH₂, benzyl and tetrazolyl; and

m is 0-4.

In one embodiment, provided herein is a compound of Formula IX

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof;

wherein

X and Y are selected as follows:

i) X is C═O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,—R^(a)OR^(b), or —R^(a)N(R^(c))(R^(d)); or

ii) X is —O—, or —N(R^(c))—; Y is hydrogen, —C(O)R^(d), alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl;

Y is optionally substituted with one to three groups Q¹;

each Q¹ is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy,cycloalkyl, heterocyclyl, aryl or heteroaryl; each Q¹ is optionallysubstituted with one to three groups Q²;

each Q² is independently alkyl, halo, haloalkyl, aryl or haloaryl;

each R^(a) is independently alkylene or a direct bond;

R^(b) is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl;

each R^(c) is independently hydrogen or alkyl;

each R^(d) is independently alkyl, aryl, cycloalkyl, heteroaryl,heterocyclyl or —R^(a)OR^(b);

each R^(d) is optionally substituted with one to three groups Q¹;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen, alkyl or cycloalkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form an optionally substituted saturated or unsaturated ringA, where substituents on ring A, when present, are selected from one tothree groups Q¹;

R³, R⁴, R⁵ and R⁶ are each independently hydrogen or alkyl;

R¹⁰ is alkylene;

Q⁵ is alkyl, halo or haloalkyl;

Z¹ is hydrogen or alkyl;

Z² is aryl, cycloalkyl, heteroaryl or heterocyclyl, each optionallysubstituted with one to four substituents Q³;

each Q³ is independently selected from alkyl, halo, cyano, cycloalkyl,heterocyclyl, aryl, heteroaryl, —R¹¹OR¹², —R¹¹OR¹¹OR¹², —R¹¹N(R¹³)(R¹⁴),—R¹¹SR¹², —R¹¹OR¹¹N(R¹³)(R¹⁴), —R¹¹C(J)N(R¹³)(R¹⁴),—R¹¹OR¹¹C(J)N(R¹³)(R¹⁴), —C(J)R¹⁵ and R¹¹S(O)_(t)R¹⁶; where each Q³ isoptionally substituted with one to three groups Q⁴, where each Q⁴ isindependently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl;

each R¹¹ is independently alkylene, alkenylene or a direct bond;

each R¹² is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

R¹³ and R¹⁴ are selected as follows:

i) R¹³ and R¹⁴ are each independently hydrogen, alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;or

ii) R¹³ and R¹⁴ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two alkyl, halo, haloalkyl, hydroxyl,alkoxy or cycloalkyl;

each R¹⁵ is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl,aryl, heteroaryl, heterocyclyl or heterocyclyl;

each R¹⁶ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

J is O or S;

t is 0-2; and

m is 0-4.

In one embodiment, provided herein is a compound of Formula IX, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein

X and Y are selected as follows:

i) X is C═O; and Y is —R^(a)OR^(b); or

ii) X is —O—; Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or—C(O)R^(d); where the alkyl and aryl groups are optionally substitutedwith one or two groups selected from alkyl and halo;

R^(a) is alkylene or a direct bond;

R^(b) is hydrogen, alkyl or aryl;

R^(d) is aryl or aryloxy;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen or alkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form a cycloalkyl ring;

R³, R⁴, R⁵ and R⁶ are each independently hydrogen or alkyl;

Q⁵ is halo;

m is 0-4;

R¹⁰ is alkylene;

Z¹ is hydrogen or alkyl;

Z² is aryl or heteroaryl, each optionally substituted with one to foursubstituents Q³;

each Q³ is independently selected from alkyl, haloalkyl, haloalkoxy,halo, cyano, aryl, heteroaryl, —R¹¹OR¹², —C(O)R¹⁵ and —C(O)NH₂;

R¹¹ is alkylene or a direct bond;

R¹² is hydrogen, alkyl or haloalkyl; and

R¹⁵ is hydroxyl or alkyl.

In one embodiment, provided herein is a compound of Formula IX, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein

X and Y are selected as follows:

i) X is C═O; and Y is —R^(a)OR^(b); or

ii) X is —O—; Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or—C(O)R^(d); where the alkyl and aryl groups are optionally substitutedwith one or two groups selected from alkyl and halo;

R^(a) is alkylene or a direct bond;

R^(b) is hydrogen, alkyl or aryl;

R^(d) is aryl or aryloxy;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen or alkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form a cycloalkyl ring;

R³, R⁴, R⁵ and R⁶ are each hydrogen;

Q⁵ is fluoro;

m is 0-4;

R¹⁰ is alkylene;

Z¹ is hydrogen or alkyl;

Z² is aryl or heteroaryl, each optionally substituted with one to foursubstituents Q³;

each Q³ is independently selected from alkyl, haloalkyl, haloalkoxy,halo, cyano, aryl, heteroaryl, —R¹¹OR¹², —C(O)R¹⁵ and —C(O)NH₂;

R¹ is alkylene or a direct bond;

R¹² is hydrogen, alkyl or haloalkyl; and

R¹⁵ is hydroxyl or alkyl.

In one embodiment, provided herein is a compound of Formula X

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof;

wherein

X and Y are selected as follows:

i) X is C═O; and Y is —R^(a)OR^(b); or

ii) X is —O—, or —N(R^(c))—; Y is hydrogen, —C(O)R^(d), alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl;

Y is optionally substituted with one to three groups Q¹;

each Q¹ is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy,cycloalkyl, heterocyclyl, aryl or heteroaryl; each Q¹ is optionallysubstituted with one to three groups Q²;

each Q² is independently alkyl, halo, haloalkyl, aryl or haloaryl;

R^(a) is alkylene or a direct bond;

R^(b) is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl;

R^(c) is hydrogen or alkyl;

R^(d) is alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or—R^(a)OR^(b);

each R^(d) is optionally substituted with one to three groups Q¹;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen, alkyl or cycloalkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form an optionally substituted saturated or unsaturated ringA, where substituents on ring A, when present, are selected from one tothree groups Q¹;

R¹⁰ is alkylene;

Q⁵ is alkyl, halo or haloalkyl;

Z¹ is hydrogen or alkyl;

Z² is aryl, cycloalkyl, heteroaryl or heterocyclyl, each optionallysubstituted with one to four substituents Q³;

each Q³ is independently selected from alkyl, halo, cyano, cycloalkyl,heterocyclyl, aryl, heteroaryl, —R¹¹OR¹², —R¹¹OR¹¹OR¹², —R¹¹N(R¹³)(R¹⁴),—R¹¹SR¹², —R¹¹OR¹¹N(R¹³)(R¹⁴), —R¹¹C(J)N(R¹³)(R¹⁴),—R¹¹OR¹¹C(J)N(R¹³)(R¹⁴), —C(J)R¹⁵ and R¹¹S(O)_(t)R¹⁶; where each Q³ isoptionally substituted with one to three groups Q⁴, where each Q⁴ isindependently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl;

each R¹¹ is independently alkylene, alkenylene or a direct bond;

each R¹² is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

R¹³ and R¹⁴ are selected as follows:

i) R¹³ and R¹⁴ are each independently hydrogen, alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;or

ii) R¹³ and R¹⁴ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two alkyl, halo, haloalkyl, hydroxyl,alkoxy or cycloalkyl;

each R¹⁵ is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl,aryl, heteroaryl, heterocyclyl or heterocyclyl;

each R¹⁶ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

J is O or S;

t is 0-2; and

m is 0-4.

In one embodiment, provided herein is a compound of Formula X or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof;

wherein

X is C═O; and Y is —OH;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen, alkyl or cycloalkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form a saturated or unsaturated ring A;

R¹⁰ is alkylene;

Q⁵ is alkyl, halo or haloalkyl;

R¹⁰ is alkylene;

Z¹ is hydrogen or alkyl;

Z² is aryl or heteroaryl, each optionally substituted with one to foursubstituents Q³;

each Q³ is independently selected from alkyl, haloalkyl, haloalkoxy,halo, cyano, aryl, heteroaryl, —R¹¹OR¹², —C(O)R¹⁵ and —C(O)NH₂;

R¹ is alkylene or a direct bond;

R¹² is hydrogen, alkyl or haloalkyl; and

R¹⁵ is hydroxyl or alkyl.

In one embodiment, provided herein is a compound of Formula X or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof;

wherein

X is C═O; and Y is —OH;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen, alkyl or cycloalkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form a saturated or unsaturated ring A;

R¹⁰ is alkylene;

Q⁵ is halo;

R¹⁰ is alkylene;

Z¹ is hydrogen or alkyl;

Z² is aryl or heteroaryl, each optionally substituted with one to foursubstituents Q³;

each Q³ is independently selected from alkyl, haloalkyl, haloalkoxy,halo, cyano, aryl, heteroaryl, —R¹¹OR¹², —C(O)R¹⁵ and —C(O)NH₂;

R¹¹ is alkylene or a direct bond;

R¹² is hydrogen, alkyl or haloalkyl; and

R¹⁵ is hydroxyl or alkyl.

In one embodiment, provided herein is a compound of Formula XI:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof;

wherein

X and Y are selected as follows:

i) X is C═O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,—R^(a)OR^(b), or —R^(a)N(R^(c))(R^(d)); or

ii) X is —O—, or —N(R^(c))—; Y is hydrogen, —C(O)R^(d), alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl;

Y is optionally substituted with one to three groups Q¹;

each Q¹ is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy,cycloalkyl, heterocyclyl, aryl or heteroaryl; each Q¹ is optionallysubstituted with one to three groups Q²;

each Q² is independently alkyl, halo, haloalkyl, aryl or haloaryl;

each R^(a) is independently alkylene or a direct bond;

R^(b) is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl;

each R^(c) is independently hydrogen or alkyl;

each R^(d) is independently alkyl, aryl, cycloalkyl, heteroaryl,heterocyclyl or —R^(a)OR^(b);

each R^(d) is optionally substituted with one to three groups Q¹;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen, alkyl or cycloalkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form an optionally substituted saturated or unsaturated ringA, where the substituents on ring A, when present, are selected from oneto three groups Q¹;

R³, R⁴, R⁵ and R⁶ are each independently hydrogen or alkyl;

R¹⁰ is alkylene;

each Q³ is independently selected from alkyl, halo, cyano, cycloalkyl,heterocyclyl, aryl, heteroaryl, —R¹¹OR¹², —R¹¹OR¹¹OR¹², —R¹¹N(R¹³)(R¹⁴),—R¹¹SR¹², —R¹¹OR¹¹N(R¹³)(R¹⁴), —R¹¹C(J)N(R¹³)(R¹⁴),—R¹¹OR¹¹C(J)N(R¹³)(R¹⁴), —C(J)R¹⁵ and R¹¹S(O)_(t)R¹⁶; where each Q³ isoptionally substituted with one to three groups Q⁴, where each Q⁴ isindependently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl;

each R¹¹ is independently alkylene, alkenylene or a direct bond;

each R¹² is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

R¹³ and R¹⁴ are selected as follows:

i) R¹³ and R¹⁴ are each independently hydrogen, alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;or

ii) R¹³ and R¹⁴ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two alkyl, halo, haloalkyl, hydroxyl,alkoxy or cycloalkyl;

each R¹⁵ is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl,aryl, heteroaryl, heterocyclyl or heterocyclyl;

each R¹⁶ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

each Q⁵ is independently alkyl, halo or haloalkyl;

J is O or S;

t is 0-2; and

m is 0-4.

In one embodiment, provided herein is a compound of Formula XI, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein

X and Y are selected as follows:

i) X is C═O; and Y is —R^(a)OR^(b); or

ii) X is —O—; Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or—C(O)R^(d); where the alkyl and aryl groups are optionally substitutedwith one or two groups selected from alkyl and halo;

R^(a) is alkylene or a direct bond;

R^(b) is hydrogen, alkyl or aryl;

R^(d) is aryl or aryloxy;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen or alkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form a cycloalkyl ring;

R³, R⁴, R⁵, and R⁶ are each independently hydrogen or alkyl;

R¹⁰ is alkylene;

Z¹ is hydrogen or alkyl;

each Q³ is independently selected from alkyl, haloalkyl, haloalkoxy,halo, cyano, aryl, heteroaryl, —R¹¹OR¹², —C(O)R¹⁵ and —C(O)NH₂;

R¹¹ is alkylene or a direct bond;

R¹² is hydrogen, alkyl or haloalkyl;

R¹⁵ is hydroxyl or alkyl;

each Q⁵ is independently alkyl, halo or haloalkyl;

m is 0-4; and

n is 0-2.

In one embodiment, provided herein is a compound of Formula XI, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein

X and Y are selected as follows:

i) X is C═O; and Y is —R^(a)OR^(b); or

ii) X is —O—; Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or—C(O)R^(d); where the alkyl and aryl groups are optionally substitutedwith one or two groups selected from alkyl and halo;

R^(a) is alkylene or a direct bond;

R^(b) is hydrogen, alkyl or aryl;

R^(d) is aryl or aryloxy;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen or alkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form a cycloalkyl ring;

R³, R⁴, R⁵ and R⁶ are each independently hydrogen or alkyl;

R¹⁰ is alkylene;

Z¹ is hydrogen or alkyl;

each Q³ is independently alkyl or halo;

each Q⁵ is independently halo or haloalkyl;

m is 0-4; and

n is 0-2.

In one embodiment, provided herein is a compound of Formula XII:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof;

wherein

X and Y are selected as follows:

i) X is C═O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,—R^(a)OR^(b), or —R^(a)N(R^(c))(R^(d)); or

ii) X is —O—, or —N(R^(c))—; Y is hydrogen, —C(O)R^(d), alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl;

Y is optionally substituted with one to three groups Q¹;

each Q¹ is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy,cycloalkyl, heterocyclyl, aryl or heteroaryl; each Q¹ is optionallysubstituted with one to three groups Q²;

each Q² is independently alkyl, halo, haloalkyl, aryl or haloaryl;

each R^(a) is independently alkylene or a direct bond;

R^(b) is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl;

each R^(c) is independently hydrogen or alkyl;

each R^(d) is independently alkyl, aryl, cycloalkyl, heteroaryl,heterocyclyl or —R^(a)OR^(b);

each R^(d) is optionally substituted with one to three groups Q¹;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen, alkyl or cycloalkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form an optionally substituted saturated or unsaturated ringA, where the substituents on ring A, when present, are selected from oneto three groups Q¹;

R³, R⁴, R⁵ and R⁶ are each independently hydrogen or alkyl;

R¹⁰ is alkylene;

each Q³ is independently selected from alkyl, halo, cyano, cycloalkyl,heterocyclyl, aryl, heteroaryl, —R¹¹OR¹², —R¹¹OR¹¹OR¹², —R¹¹N(R¹³)(R¹⁴),—R¹¹SR¹², —R¹¹OR¹¹N(R¹³)(R¹⁴), —R¹¹C(J)N(R¹³)(R¹⁴),—R¹¹OR¹¹C(J)N(R¹³)(R¹⁴), —C(J)R¹⁵ and R¹¹S(O)_(t)R¹⁶; where each Q³ isoptionally substituted with one to three groups Q⁴, where each Q⁴ isindependently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl;

each R¹¹ is independently alkylene, alkenylene or a direct bond;

each R¹² is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

R¹³ and R¹⁴ are selected as follows:

i) R¹³ and R¹⁴ are each independently hydrogen, alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;or

ii) R¹³ and R¹⁴ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two alkyl, halo, haloalkyl, hydroxyl,alkoxy or cycloalkyl;

each R¹⁵ is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl,aryl, heteroaryl, heterocyclyl or heterocyclyl;

each R¹⁶ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

each Q⁵ is independently alkyl, halo or haloalkyl;

J is O or S;

t is 0-2.

In one embodiment, provided herein is a compound of Formula XII, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein

X and Y are selected as follows:

i) X is C═O; and Y is —R^(a)OR^(b); or

ii) X is —O—; Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or—C(O)R^(d); where the alkyl and aryl groups are optionally substitutedwith one or two groups selected from alkyl and halo;

R^(a) is alkylene or a direct bond;

R^(b) is hydrogen, alkyl or aryl;

each R^(d) is aryl or aryloxy;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen or alkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form a cycloalkyl ring;

R³, R⁴, R⁵, and R⁶ are each independently hydrogen or alkyl;

R¹⁰ is alkylene;

Z¹ is hydrogen or alkyl;

each Q³ is independently selected from alkyl, haloalkyl, haloalkoxy,halo, cyano, aryl, heteroaryl, —R¹¹OR¹², —C(O)R¹⁵ and —C(O)NH₂;

R¹ is alkylene or a direct bond;

R¹² is hydrogen, alkyl or haloalkyl;

R¹⁵ is hydroxyl or alkyl; and

each Q⁵ is independently alkyl, halo or haloalkyl.

In one embodiment, provided herein is a compound of Formula XII, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein

X and Y are selected as follows:

i) X is C═O; and Y is —R^(a)OR^(b); or

ii) X is —O—; Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or—C(O)R^(d); where the alkyl and aryl groups are optionally substitutedwith one or two groups selected from alkyl and halo;

R^(a) is alkylene or a direct bond;

R^(b) is hydrogen, alkyl or aryl;

R^(d) is aryl or aryloxy;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen or alkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form a cycloalkyl ring;

R³, R⁴, R⁵ and R⁶ are each independently hydrogen or alkyl;

R¹⁰ is alkylene;

Z¹ is hydrogen or alkyl;

each Q³ is independently alkyl or halo; and

each Q⁵ is independently halo or haloalkyl.

In one embodiment, provided herein is a compound of Formula XIII

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof;

wherein

X and Y are selected as follows:

i) X is C═O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,—R^(a)OR^(b), or —R^(a)N(R^(c))(R^(d)); or

ii) X is —O—, or —N(R^(c))—; Y is hydrogen, —C(O)R^(d), alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl;

Y is optionally substituted with one to three groups Q¹;

each Q¹ is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy,cycloalkyl, heterocyclyl, aryl or heteroaryl; each Q¹ is optionallysubstituted with one to three groups Q²;

each Q² is independently alkyl, halo, haloalkyl, aryl or haloaryl;

each R^(a) is independently alkylene or a direct bond;

R^(b) is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl;

each R^(c) is independently hydrogen or alkyl;

each R^(d) is independently alkyl, aryl, cycloalkyl, heteroaryl,heterocyclyl or —R^(a)OR^(b);

each R^(d) is optionally substituted with one to three groups Q¹;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen, alkyl or cycloalkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form an optionally substituted saturated or unsaturated ringA, where substituents on ring A, when present, are selected from one tothree groups Q¹;

R³, R⁴, R⁵ and R⁶ are each independently hydrogen or alkyl;

R¹⁰ is alkylene;

Q⁵ is alkyl, halo or haloalkyl;

Z¹ is hydrogen or alkyl;

Z² is aryl, cycloalkyl, heteroaryl or heterocyclyl, each optionallysubstituted with one to four substituents Q³;

each Q³ is independently selected from alkyl, halo, cyano, cycloalkyl,heterocyclyl, aryl, heteroaryl, —R¹¹OR¹², —R¹¹OR¹¹OR¹², —R¹¹N(R¹³)(R¹⁴),—R¹¹SR¹², —R¹¹OR¹¹N(R¹³)(R¹⁴), —R¹¹C(J)N(R¹³)(R¹⁴),—R¹¹OR¹¹C(J)N(R¹³)(R¹⁴), —C(J)R¹⁵ and R¹¹S(O)_(t)R¹⁶; where each Q³ isoptionally substituted with one to three groups Q⁴, where each Q⁴ isindependently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl;

each R¹¹ is independently alkylene, alkenylene or a direct bond;

each R¹² is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

R¹³ and R¹⁴ are selected as follows:

i) R¹³ and R¹⁴ are each independently hydrogen, alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;or

ii) R¹³ and R¹⁴ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two alkyl, halo, haloalkyl, hydroxyl,alkoxy or cycloalkyl;

each R¹⁵ is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl,aryl, heteroaryl, heterocyclyl or heterocyclyl;

each R¹⁶ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

J is O or S;

t is 0-2; and

m is 0-4.

In one embodiment, provided herein is a compound of Formula XIII, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein

X and Y are selected as follows:

i) X is C═O; and Y is —R^(a)OR^(b); or

ii) X is —O—; Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or—C(O)R^(d); where the alkyl and aryl groups are optionally substitutedwith one or two groups selected from alkyl and halo;

R^(a) is alkylene or a direct bond;

R^(b) is hydrogen, alkyl or aryl;

R^(d) is aryl or aryloxy;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen or alkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form a cycloalkyl ring;

R³, R⁴, R⁵ and R⁶ are hydrogen;

Q⁵ is haloalkyl;

m is 0-4;

R¹⁰ is alkylene;

R³, Y¹, Y² and Y³ are selected as follows:

i) Y¹ together with R³ forms an optionally substituted saturated orunsaturated ring B, where substituents on ring B, when present, areselected from one to three groups Q¹;

Y² is absent, hydrogen or alkyl; and

Y³ is absent, hydrogen or alkyl; or

ii) R³ is hydrogen or alkyl; Y¹ and Y² together are ═O; and Y³ is—N(Z¹)(Z²);

Z¹ is hydrogen or alkyl;

Z² is aryl or heteroaryl, each optionally substituted with one to foursubstituents Q³;

each Q³ is independently selected from alkyl, haloalkyl, haloalkoxy,halo, cyano, aryl, heteroaryl, —R¹¹OR¹², —C(O)R¹⁵ and —C(O)NH₂;

R¹ is alkylene or a direct bond;

R¹² is hydrogen, alkyl or haloalkyl; and

R¹⁵ is hydroxyl or alkyl.

In one embodiment, provided herein is a compound of Formula XIII, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein Q⁵ is trifluoroalkyl, and the remaining variables areas described elsewhere herein.

In one embodiment, provided herein is a compound of Formula I, II, III,IV, V, VI, VII, VIII, IX, X, XI, XII or XIII or an enantiomer or amixture of enantiomers thereof, or a pharmaceutically acceptable salt,solvate, hydrate, co-crystal, clathrate, or polymorph thereof, whereinR¹⁰ is —CH₂— or —CH₂—CH₂—, and the remaining substituents are asdescribed elsewhere herein.

In one embodiment, provided herein is a compound of Formula I, II, III,IV, V, VI, VII or VIII, IX, X, XI, XII or XIII or an enantiomer or amixture of enantiomers thereof, or a pharmaceutically acceptable salt,solvate, hydrate, co-crystal, clathrate, or polymorph thereof, whereinR¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen or methyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form a cyclopentyl ring; and the remaining substituents areas described elsewhere herein.

In one embodiment, provided herein is a compound of Formula I or II, oran enantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein R⁹ is aryl or heteroaryl, each optionally substitutedwith one to four substituents selected from halo, alkyl and haloalkyl;and the remaining substituents are as described elsewhere herein.

In one embodiment, provided herein is a compound of Formula I or II, oran enantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein R⁹ is phenyl or pyrimidinyl, each optionallysubstituted with one to four substituents selected from halo, alkyl andhaloalkyl; and the remaining substituents are as described elsewhereherein.

In one embodiment, provided herein is a compound of Formula I, II, III,IV, VI, VII or VIII, or an enantiomer or a mixture of enantiomersthereof, or a pharmaceutically acceptable salt, solvate, hydrate,co-crystal, clathrate, or polymorph thereof, wherein Z² is selected from6-10 membered aryl or heteroaryl; each optionally substituted with oneor two Q³ groups, and each Q³ is independently selected from halo,alkyl, haloalkyl, arylalkyl, alkoxy, alkylcarbonyl, haloalkoxy, cyano,aryl, heteroaryl and aminocarbonyl, and the remaining substituents areas described elsewhere herein.

In one embodiment, provided herein is a compound of Formula I, II, III,IV or V, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein R¹⁰ is —CH₂— or —CH₂—CH₂—; andZ² is selected from 6-10 membered aryl or heteroaryl; each optionallysubstituted with one or two Q³ groups, and each Q³ is independentlyselected from halo, alkyl, haloalkyl, arylalkyl, alkoxy, alkylcarbonyl,haloalkoxy, cyano, aryl, heteroaryl and aminocarbonyl, and the remainingsubstituents are as described elsewhere herein.

In one embodiment, provided herein is a compound of Formula I, II, III,IV or V, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein R¹⁰ is —CH₂— or —CH₂—CH₂—; andZ² is selected from 6-10 membered aryl or heteroaryl; each optionallysubstituted with one or two Q³ groups, and each Q³ is independentlyselected from halo, alkyl, haloalkyl, arylalkyl, alkoxy, alkylcarbonyl,haloalkoxy, cyano, aryl, heteroaryl and aminocarbonyl, where theheteroaryl contains one or two heteroatoms selected from nitrogen andsulfur, and the remaining substituents are as described elsewhereherein.

In one embodiment, provided herein is a compound of Formula I, II, III,IV, VI, VII or VIII, or an enantiomer or a mixture of enantiomersthereof, or a pharmaceutically acceptable salt, solvate, hydrate,co-crystal, clathrate, or polymorph thereof, wherein Z² is selected fromphenyl, pyridinyl, pyrimidyl, naphthyl, indazolyl, quinolinyl,isoquinolynyl and benzoisothiazolyl; each optionally substituted withone or two Q³ groups, and each Q³ is independently selected from halo,alkyl, haloalkyl, arylalkyl, alkoxy, alkylcarbonyl, haloalkoxy, cyano,aryl, heteroaryl and aminocarbonyl, and the remaining substituents areas described elsewhere herein.

In one embodiment, provided herein is a compound of Formula I, II, IIIor VI, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein R¹⁰ is —CH₂— or —CH₂—CH₂—; andZ² is selected from phenyl, pyridinyl, pyrimidyl, naphthyl, indazolyl,quinolinyl, isoquinolynyl and benzoisothiazolyl; each optionallysubstituted with one or two Q³ groups, and each Q³ is independentlyselected from halo, alkyl, haloalkyl, arylalkyl, alkoxy, alkylcarbonyl,haloalkoxy, cyano, aryl, heteroaryl and aminocarbonyl, and the remainingsubstituents are as described elsewhere herein.

In one embodiment, provided herein is a compound of Formula I, II, III,IV, VI, VII or VIII, or an enantiomer or a mixture of enantiomersthereof, or a pharmaceutically acceptable salt, solvate, hydrate,co-crystal, clathrate, or polymorph thereof, wherein Z² is selected fromphenyl, pyridinyl, pyrimidyl, naphthyl, indazolyl, quinolinyl,isoquinolynyl and benzoisothiazolyl; each optionally substituted withone or two Q³ groups, and each Q³ is independently selected from chloro,fluoro, methyl, methoxy, trifluoromethoxy, —C(O)CH₃, cyano, —C(O)NH₂,benzyl and tetrazolyl, and the remaining substituents are as describedelsewhere herein.

In one embodiment, provided herein is a compound of Formula I, II, IIIor IV, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein R¹⁰ is —CH₂— or —CH₂—CH₂—; andZ² is selected from phenyl, pyridinyl, pyrimidyl, naphthyl, indazolyl,quinolinyl, isoquinolynyl and benzoisothiazolyl; each optionallysubstituted with one or two Q³ groups, and each Q³ is independentlyselected from chloro, fluoro, methyl, methoxy, trifluoromethoxy,—C(O)CH₃, cyano, —C(O)NH₂, benzyl and tetrazolyl, and the remainingsubstituents are as described elsewhere herein.

In one embodiment, provided herein is a compound of Formula XIV:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof;

wherein

X is C═O;

Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —R^(a)OR^(b), or—R^(a)N(R^(c))(R^(d)); each optionally substituted with one to threegroups Q¹;

each Q¹ is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy,cycloalkyl, heterocyclyl, aryl or heteroaryl; each Q¹ is optionallysubstituted with one to three groups Q²;

each Q² is independently alkyl, halo, haloalkyl, aryl or haloaryl;

each R^(a) is independently alkylene or a direct bond;

R^(b) is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl;

each R^(c) is independently hydrogen or alkyl;

R^(d) is alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or—R^(a)OR^(b);

each R^(d) is optionally substituted with one to three groups Q¹;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen, alkyl or cycloalkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form an optionally substituted saturated or unsaturated ringA, where the substituents on ring A, when present, are selected from oneto three groups Q¹;

R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently hydrogen or alkyl;

R⁹ is aryl or heteroaryl, each optionally substituted with one to foursubstituents Q¹;

R¹⁰ is alkylene;

each Q³ is independently selected from alkyl, halo, cyano, cycloalkyl,heterocyclyl, aryl, heteroaryl, —R¹¹OR¹², —R¹¹OR¹¹OR¹², —R¹¹N(R¹³)(R¹⁴),—R¹¹SR¹², —R¹¹OR¹¹N(R¹³)(R¹⁴), —R¹¹C(J)N(R¹³)(R¹⁴),—R¹¹OR¹¹C(J)N(R¹³)(R¹⁴), —C(J)R¹⁵ and R¹¹S(O)_(t)R¹⁶; where each Q³ isoptionally substituted with one to three groups Q⁴, where each Q⁴ isindependently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl;

each R¹¹ is independently alkylene, alkenylene or a direct bond;

each R¹² is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

R¹³ and R¹⁴ are selected as follows:

i) R¹³ and R¹⁴ are each independently hydrogen, alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;or

ii) R¹³ and R¹⁴ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two alkyl, halo, haloalkyl, hydroxyl,alkoxy or cycloalkyl;

each R¹⁵ is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl,aryl, heteroaryl, heterocyclyl or heterocyclyl;

each R¹⁶ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

J is O or S;

t is 0-2; and

n is 0-3.

In one embodiment, provided herein is a compound of Formula XIV or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof;

wherein

X is C═O;

Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —R^(a)OR^(b), or—R^(a)N(R^(c))(R^(d)); each optionally substituted with one to threegroups Q¹;

each Q¹ is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy,cycloalkyl, heterocyclyl, aryl or heteroaryl; each Q¹ is optionallysubstituted with one to three groups Q²;

each Q² is independently alkyl, halo, haloalkyl, aryl or haloaryl;

each R^(a) is independently alkylene or a direct bond;

R^(b) is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl;

each R^(c) is independently hydrogen or alkyl;

R^(d) is alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or—R^(a)OR^(b);

each R^(d) is optionally substituted with one to three groups Q¹;

R¹ and R² are selected as follows:

i) R¹ and R² are each independently hydrogen, alkyl or cycloalkyl; or

ii) R¹ and R² together with the carbon atom on which they aresubstituted form an optionally substituted saturated or unsaturated ringA, where the substituents on ring A, when present, are selected from oneto three groups Q¹;

R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently hydrogen or alkyl;

R⁹ is aryl or heteroaryl, each optionally substituted with one to foursubstituents Q¹;

R¹⁰ is alkylene;

each Q³ is independently selected from alkyl, halo, cyano, cycloalkyl,heterocyclyl, aryl, heteroaryl, —R¹¹OR¹², —R¹¹OR¹¹OR¹², —R¹¹N(R¹³)(R¹⁴),—R¹¹SR¹², —R¹¹OR¹¹N(R¹³)(R¹⁴), —R¹¹C(J)N(R¹³)(R¹⁴),—R¹¹OR¹¹C(J)N(R¹³)(R¹⁴), —C(J)R¹⁵ and R¹¹S(O)_(t)R¹⁶; where each Q³ isoptionally substituted with one to three groups Q⁴, where each Q⁴ isindependently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl;

each R¹¹ is independently alkylene, alkenylene or a direct bond;

each R¹² is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

R¹³ and R¹⁴ are selected as follows:

i) R¹³ and R¹⁴ are each independently hydrogen, alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;or

ii) R¹³ and R¹⁴ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two alkyl, halo, haloalkyl, hydroxyl,alkoxy or cycloalkyl;

each R¹⁵ is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl,aryl, heteroaryl, heterocyclyl or heterocyclyl;

each R¹⁶ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

J is O or S;

t is 0-2; and

n is 0-3.

In one embodiment, provided herein is a compound of Formula XIV or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof;

wherein

X is C═O; and Y is —R^(a)OR^(b);

R^(a) is alkylene or a direct bond;

R^(b) is hydrogen or alkyl;

R¹ and R² are each hydrogen;

R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently hydrogen or alkyl;

R⁹ is aryl or heteroaryl, each optionally substituted with one to fourhalo;

R¹⁰ is alkylene;

each Q³ is halo; and

n is 0-3.

In one embodiment, provided herein is a compound of Formula XV:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof; where the variables are as describedelsewhere herein.

In one embodiment, provided herein is a compound of Formula XV or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof;

wherein

X is C═O; and Y is —R^(a)OR^(b);

R^(a) is alkylene or a direct bond;

R^(b) is hydrogen or alkyl;

R⁹ is aryl or heteroaryl, each optionally substituted with one to fourhalo; and Q³ is halo.

In one embodiment, provided herein is a compound of Formula XVI:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof; where each Q⁷ is halo, x is 0-4 and theremaining variables are as described elsewhere herein.

In one embodiment, provided herein is a compound of Formula XI or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof;

wherein

X is C═O; and Y is —R^(a)OR^(b);

R^(a) is alkylene or a direct bond;

R^(b) is hydrogen or alkyl;

R¹ and R² are each hydrogen;

R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently hydrogen or alkyl;

each Q⁷ is halo;

R¹⁰ is alkylene;

each Q³ is halo;

x is 0-4; and

n is 0-3.

In one embodiment, provided herein is a compound of Formula XVII:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof; where each Q⁷ is halo, x is 0-4 and theremaining variables are as described elsewhere herein.

In one embodiment, provided herein is a compound of Formula XVII or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof;

wherein

Y is —R^(a)OR^(b);

R^(a) is alkylene or a direct bond;

R^(b) is hydrogen or alkyl;

each Q⁷ is halo;

each Q³ is halo;

x is 0-4; and

n is 0-3.

In one embodiment, provided herein is a compound of Formula XVIII:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof; where each Q⁷ is halo, and theremaining variables are as described elsewhere herein.

In one embodiment, provided herein is a compound of Formula XVIII or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof;

wherein

X is C═O; and Y is —R^(a)OR^(b);

R^(a) is alkylene or a direct bond;

R^(b) is hydrogen or alkyl;

R¹ and R² are each hydrogen;

R⁴, R⁵ and R⁶ are each independently hydrogen or alkyl;

each Q⁷ is halo;

R¹⁰ is alkylene;

each Q³ is halo; and

n is 0-3.

In one embodiment, provided herein is a compound of Formula XIX:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof; where each Q⁷ is halo, and theremaining variables are as described elsewhere herein.

In one embodiment, provided herein is a compound of Formula XIX or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof;

wherein

Y is —R^(a)OR^(b);

R^(a) is alkylene or a direct bond;

R^(b) is hydrogen or alkyl;

each Q⁷ is halo; and

each Q³ is halo.

In one embodiment, provided herein is a compound of Formula XIX or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof;

wherein

Y is —R^(a)OR^(b);

R^(a) is alkylene or a direct bond;

R^(b) is hydrogen or alkyl;

each Q⁷ is fluoro; and

each Q³ is chloro.

6.3. Methods of Treatment

The compounds provided herein are used in methods for the treatment ofconditions that are associated with or modulated by caspase-1, caspase-4and/or caspase-5.

Accordingly, in one embodiment provided herein is a method for treatingor preventing a disease modulated by caspase-1, caspase-4 and/orcaspase-5 in a subject comprising administering to the subject acompound provided herein.

The disease states which can be treated or prevented by the compoundsand/or their pharmaceutical compositions provided herein include, butare not limited to, inflammatory diseases, autoimmune diseases,proliferative disorders, infectious diseases, and degenerative diseases.

In one embodiment, the inflammatory diseases which can be treated orprevented by the compounds and/or their pharmaceutical compositionsprovided herein include, but are not limited to, osteoarthritis, acutepancreatitis, chronic pancreatitis, asthma, and adult respiratorydistress syndrome.

In one embodiment, the inflammatory diseases which can be treated orprevented by the compounds and/or their pharmaceutical compositionsprovided herein include, but are not limited to, chronic and acutediseases such as, for example, autoinflammatory diseases such asCryopyrin-Associated Periodic Syndromes (CAPS) and neuroinflammatorydiseases such as multiple sclerosis (MS), Parkinson's disease andAlzheimer's disease. Treatment of acute inflammatory diseases such as,for example, septic shock, septicemia and adult respiratory distresssyndrome also are contemplated by the methods provided herein.

In one embodiment, the autoimmune diseases which can be treated orprevented by the compounds and/or their pharmaceutical compositionsprovided herein include, but are not limited to, glomerulonephritis,rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronicthyroiditis, Graves' disease, autoimmune gastritis, insulin-dependentdiabetes mellitus (Type I), autoimmune hemolytic anemia, autoimmuneneutropenia, thrombocytopenia, chronic active hepatitis, myastheniagravis, multiple sclerosis, inflammatory bowel disease, Crohn's disease,psoriasis, atopic dermatitis and graft vs. host disease.

In one embodiment, the diseases which can be treated or prevented by thecompounds and/or their pharmaceutical compositions provided hereininclude, but are not limited to, destructive bone disorders, such asosteoporosis and multiple myeloma-related bone disorder.

In one embodiment, the disease which can be treated or prevented by thecompounds and/or their pharmaceutical compositions provided hereininclude, but are not limited to, infectious diseases such as sepsis,septic shock, and Shigellosis.

In one embodiment, the degenerative diseases which can be treated orprevented by the compounds and/or their pharmaceutical compositionsprovided herein include, but are not limited to, Alzheimer's disease,Parkinson's disease, cerebral ischemia, myocardial ischemia, spinalmuscular atrophy, multiple sclerosis, AIDS-related encephalitis,HIV-related encephalitis, aging, alopecia, and neurological damage dueto stroke.

Other diseases having an inflammatory or apoptotic component can betreated or prevented by the compounds provided herein. Such diseases maybe systemic diseases or diseases with effects localized in the liver orother organs and may be caused by, for example, excess dietary alcoholintake or viruses, such as HBV, HCV, HGV, yellow fever virus, denguefever virus, and Japanese encephalitis virus.

In one embodiment provided herein is a method for treating or preventinga disease in a subject comprising administering to the subject acompound provided herein, where the disease is selected frominflammation or inflammatory diseases, inflammatory bowel disease,sepsis and septic shock, degenerative diseases including Alzheimer'sdisease, Huntingtons' disease, Parkinsons' disease, Multiple sclerosis,amyotrophic lateral sclerosis, spinobulbar atrophy, prion disease,dementia; brain hypoxia, anoxia, hyperoxia; ischemic multifocal lesionsinvolving the cortical or lenticulo striate branches of the MCA,ischemic lesions in the territory of the middle cerebral artery (MCA) orleft cerebral hemisphere, caused by haemodynamic differences from apatent ductus arteriosus, or a more direct route involving the leftcommon carotid; focal arterial infarction, retinal pericyte apoptosis,retinal neurons apoptosis glaucoma, retinal degenerative diseases, agerelated macular degeneration (AMD) retinal damages resulting from localischemia, diabetic retinopaty, epilepsy, apoptosis during spinal cordinjury, apoptosis resulting from traumatic brain injury, retinalischemia, apoptosis during pathological situations of focal cerebralischemia, cytotoxic T cell and natural killer cell-mediated apoptosisassociated with autoimmune disease and transplant rejection, cell deathof cardiac cells including heart failure, cardiomyopathy, viralinfection or bacterial infection of heart, myocardial ischemia,myocardial infarct, and myocardial ischemia, coronary artery by-passgraft, mitochondrial drug toxicity e.g. as a result of chemotherapy orHIV therapy, cell death during viral infection or bacterial infection,cell death from follicle to ovocyte stages, from ovocyte to mature eggstages and sperm (for example, methods of freezing and transplantingovarian tissue, artificial fecondation), or to preserve fertility inwomen and men after chemotherapy, or to preserve fertility in femalesand males animals, macular degenerescence and glaucoma, acute hepatitis,chronic active hepatitis, hepatitis-B, and hepatitis-C, hair loss, andsaid hair loss due-to male-pattern baldness, radiation, chemotherapy oremotional stress, skin damage (due to exposure to high level ofradiation, heat, burns, chemicals, sun, and autoimmune diseases), celldeath of bone marrow cells in myelodysplastic symdromes (MDS),pancreatisis, respiratory symdrome, or osteoarthitis, rheumatoidarthritis, psoriasis, glomerulonephritis, atheroscerosis, and graftversus host disease, disease states associated with an increase ofinflammation.

In some embodiments, provided herein is a method for use of a compoundherein for the treatment and/or prevention of cancers. Typical cancersinclude lung cancer, colorectal cancer (CRC), melanoma, gastric cancer(including esophageal cancer), renal cell carcinoma (RCC), breastcancer, prostate cancer, head and neck cancer, bladder cancer,hepatocellular carcinoma (HCC), ovarian cancer, cervical cancer,endometrial cancer, pancreatic cancer, neuroendocrine cancer,hematological cancer (particularly multiple myeloma, acute myeloblasticleukemia (AML), and biliary tract cancer.

In one embodiment, provided herein is a therapy to improve the treatmentof cancer having at least a partial inflammatory basis, e.g., a cancerdescribed herein such as lung cancer. In one embodiment, provided hereinis a use of a compound herein for the treatment and/or prevention ofcancer having at least a partial inflammatory basis, e.g., a cancerdescribed herein such as lung cancer. In another aspect, provided hereinis a particular clinical dosage regimen for the administration of acompound herein for the treatment and/or prevention of cancer. Inanother aspect the subject with cancer having at least a partialinflammatory basis, including lung cancer, is administered with one ormore therapeutic agent (e.g., a chemotherapeutic agent) and/or havereceived/will receive debulking procedures in addition to theadministration of a compound herein.

In some embodiments, the methods of treating or preventing cancer in ahuman subject in need thereof comprising administering to the subject atherapeutically effective amount of a compound provided herein.

Another aspect of the invention is the use of a compound herein for thepreparation of a medicament for the treatment of cancer.

In some embodiments, the compounds herein are used for the treatment orprevention in in cryopyrin-associated periodic syndromes (CAPS),familial Mediterranean fever (FMF), systemic onset juvenile idiopathicarthritis (SJIA), hyperimmunoglobulin D syndrome (HIDS) and tumornecrosis factor receptor-associated periodic syndrome (TRAPS), familialcold urticaria, neonatal onset multisystem inflammatory disease, SJIAand FMF, and Muckle Wells syndrome.

In some embodiments, the compounds provided herein may be used in any ofthe above-mentioned methods.

6.4. Pharmaceutical Compositions

The pharmaceutical compositions provided herein contain therapeuticallyeffective amounts of one or more of the compounds provided herein thatare useful in the prevention, treatment, or amelioration of one or moreconditions associated with or modulated by caspase-1, caspase-4 and/orcaspase-5, or one or more symptoms of a condition associated with ormodulated by caspase-1, caspase-4 and/or caspase-5, such as thosedescribed in Section 4.4, and a pharmaceutically acceptable carrier.

The compounds can be formulated into suitable pharmaceuticalpreparations such as solutions, suspensions, tablets, dispersibletablets, pills, capsules, powders, sustained release formulations orelixirs, for oral administration or in sterile solutions or suspensionsfor parenteral administration, as well as transdermal patch preparationand dry powder inhalers. In one embodiment, the compounds providedherein are formulated into pharmaceutical compositions using techniquesand procedures well known in the art (see, e.g., Remington'sPharmaceutical Sciences, 20^(th) eds., Mack Publishing, Easton Pa.(2000)).

In the compositions, effective concentrations of one or more compoundsor pharmaceutically acceptable derivatives is (are) mixed with asuitable pharmaceutical carrier or vehicle. The compounds can bederivatized as the corresponding salts, esters, acids, bases, solvates,hydrates or prodrugs prior to formulation, as described above. Theconcentrations of the compounds in the compositions are effective fordelivery of an amount, upon administration, that treats, prevents, orameliorates a condition or one or more of the symptoms of a conditionmodulated by one or more caspases as described in Section 4.4.

In one embodiment, the compositions are formulated for single dosageadministration. To formulate a composition, the weight fraction ofcompound is dissolved, suspended, dispersed or otherwise mixed in aselected vehicle at an effective concentration such that the treatedcondition is relieved or ameliorated. Pharmaceutical carriers orvehicles suitable for administration of the compounds provided hereininclude any such carriers known to those skilled in the art to besuitable for the particular mode of administration.

In addition, the compounds can be formulated as the solepharmaceutically active ingredient in the composition or can be combinedwith other active ingredients. Liposomal suspensions, includingtissue-targeted liposomes, such as tumor-targeted liposomes, can also besuitable as pharmaceutically acceptable carriers. These can be preparedaccording to methods known to those skilled in the art. For example,liposome formulations can be prepared as known in the art. Briefly,liposomes such as multilamellar vesicles (MLV's) can be formed by dryingdown egg phosphatidyl choline and brain phosphatidyl serine (7:3 molarratio) on the inside of a flask. A solution of a compound providedherein in phosphate buffered saline (PBS) lacking divalent cations isadded and the flask shaken until the lipid film is dispersed. Theresulting vesicles are washed to remove unencapsulated compound,pelleted by centrifugation, and then resuspended in PBS.

The active compound is included in the pharmaceutically acceptablecarrier in an amount sufficient to exert a therapeutically useful effectin the absence of undesirable side effects on the patient treated. Thetherapeutically effective concentration can be determined empirically bytesting the compounds in in vitro and in vivo systems known in the artand then extrapolated therefrom for dosages for humans.

The concentration of active compound in the pharmaceutical compositionwill depend on absorption, inactivation and excretion rates of theactive compound, the physicochemical characteristics of the compound,the dosage schedule, and amount administered as well as other factorsknown to those of skill in the art.

In one embodiment, a therapeutically effective dosage should produce aserum concentration of an active ingredient of from about 0.1 ng/ml toabout 50-100 μg/ml, from about 0.5 ng/ml to about 80 μg/ml, from about 1ng/ml to about 60 μg/ml, from about 5 ng/ml to about 50 μg/ml, fromabout 5 ng/ml to about 40 μg/ml, from about 10 ng/ml to about 35 μg/ml,from about 10 ng/ml to about 25 μg/ml, from about 10 ng/ml to about 10μg/ml, from about 25 ng/ml to about 10 μg/ml, from about 50 ng/ml toabout 10 μg/ml, from about 50 ng/ml to about 5 g/ml, from about 100ng/ml to about 5 μg/ml, from about 200 ng/ml to about 5 μg/ml, fromabout 250 ng/ml to about 5 μg/ml, from about 500 ng/ml to about 5 μg/ml,from about 1 μg/ml to about 50 μg/ml, from about 0.1 ng/ml to about 5ng/ml, from about 1 ng/ml to about 10 ng/ml or from about 1 μg/ml toabout 10 μg/ml. The pharmaceutical compositions, in certain embodiments,should provide a dosage of from about 0.001 mg to about 2000 mg ofcompound per kilogram of body weight per day, from about 0.002 mg toabout 1000 mg of compound per kilogram of body weight per day, fromabout 0.005 mg to about 500 mg of compound per kilogram of body weightper day, from about 0.005 mg to about 250 mg of compound per kilogram ofbody weight per day, from about 0.005 mg to about 200 mg of compound perkilogram of body weight per day, from about 0.005 mg to about 100 mg ofcompound per kilogram of body weight per day, from about 0.001 mg toabout 0.005 mg of compound per kilogram of body weight per day, fromabout 0.01 mg to about 100 mg of compound per kilogram of body weightper day, from about 0.02 mg to about 100 mg of compound per kilogram ofbody weight per day, from about 0.05 mg to about 100 mg of compound perkilogram of body weight per day, from about 0.1 mg to about 100 mg ofcompound per kilogram of body weight per day, from about 0.5 mg to about100 mg of compound per kilogram of body weight per day, from about 0.75mg to about 100 mg of compound per kilogram of body weight per day, fromabout 1 mg to about 100 mg of compound per kilogram of body weight perday, from about 1 mg to about 10 mg of compound per kilogram of bodyweight per day, from about 0.001 mg to about 5 mg of compound perkilogram of body weight per day, from about 200 mg to about 2000 mg ofcompound per kilogram of body weight per day, or from about 10 mg toabout 100 mg of compound per kilogram of body weight per day.Pharmaceutical dosage unit forms are prepared to provide from about 1 mgto about 1000 mg, from about 1 mg to about 800 mg, from about 5 mg toabout 800 mg, from about 1 mg to about 100 mg, from about 1 mg to about50 mg, from about 5 mg to about 100 mg, from about 10 mg to about 50 mg,from about 10 mg to about 100 mg, from about 25 mg to about 50 mg, andfrom about 10 mg to about 500 mg of the essential active ingredient or acombination of essential ingredients per dosage unit form.

The active ingredient can be administered at once, or can be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment is afunction of the disease being treated and can be determined empiricallyusing known testing protocols or by extrapolation from in vivo or invitro test data. It is to be noted that concentrations and dosage valuescan also vary with the severity of the condition to be alleviated. It isto be further understood that for any particular subject, specificdosage regimens should be adjusted over time according to the individualneed and the professional judgment of the person administering orsupervising the administration of the compositions, and that theconcentration ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed compositions.

Pharmaceutically acceptable derivatives include acids, bases and esters,salts, esters, hydrates, solvates and prodrug forms. The derivative isselected such that its pharmacokinetic properties are superior to thecorresponding neutral compound.

Thus, effective concentrations or amounts of one or more of thecompounds described herein or pharmaceutically acceptable derivativesthereof are mixed with a suitable pharmaceutical carrier or vehicle forsystemic, topical or local administration to form pharmaceuticalcompositions. Compounds are included in an amount effective forameliorating one or more symptoms of, or for treating or preventingrecurrence of a condition associated with or modulated by caspase-1,caspase-4 and/or caspase-5, such as those described in Section 4.4. Theconcentration of active compound in the composition will depend onabsorption, inactivation, excretion rates of the active compound, thedosage schedule, amount administered, particular formulation as well asother factors known to those of skill in the art.

The compositions are intended to be administered by a suitable route,including orally, parenterally, intravitreal injection, impregnatedcontact lens, rectally, topically, locally, by inhalation spray,nasally, buccally, vaginally, by an implanted reservoir or vianasogastric or orogastric tube. In some embodiments, administration isby an oral route. In other embodiments, administration is by aparenteral route. For oral administration, capsules and tablets can beused. The compositions are in liquid, semi-liquid or solid form and areformulated in a manner suitable for each route of administration. In oneembodiment, modes of administration include parenteral and oral modes ofadministration. In certain embodiments, oral administration iscontemplated.

Solutions or suspensions used for parenteral, intravitreal, intradermal,subcutaneous, or topical application can include any of the followingcomponents: a sterile diluent, such as water for injection, salinesolution, fixed oil, polyethylene glycol, glycerine, propylene glycol,dimethyl acetamide or other synthetic solvent; antimicrobial agents,such as benzyl alcohol and methyl parabens; antioxidants, such asascorbic acid and sodium bisulfite; chelating agents, such asethylenediaminetetraacetic acid (EDTA); buffers, such as acetates,citrates and phosphates; and agents for the adjustment of tonicity suchas sodium chloride or dextrose. Parenteral preparations can be enclosedin ampules, disposable syringes or single or multiple dose vials made ofglass, plastic or other suitable material.

In instances in which the compounds exhibit insufficient solubility,methods for solubilizing compounds can be used. Such methods are knownto those of skill in this art, and include, but are not limited to,using co-solvents, such as dimethyl sulfoxide (DMSO), using surfactants,such as TWEEN®, or dissolution in aqueous sodium bicarbonate.

Upon mixing or addition of the compound(s), the resulting mixture can bea solution, suspension, emulsion or the like. The form of the resultingmixture depends upon a number of factors, including the intended mode ofadministration and the solubility of the compound in the selectedcarrier or vehicle. The effective concentration is sufficient forameliorating the symptoms of the disease, disorder or condition treatedand can be empirically determined.

The pharmaceutical compositions are provided for administration tohumans and animals in unit dosage forms, such as tablets, capsules,pills, powders, granules, sterile parenteral solutions or suspensions,and oral solutions or suspensions, and oil/water emulsions containingsuitable quantities of the compounds or pharmaceutically acceptablederivatives thereof. The pharmaceutically therapeutically activecompounds and derivatives thereof are formulated and administered inunit dosage forms or multiple dosage forms. Unit dose forms as usedherein refer to physically discrete units suitable for human and animalsubjects and packaged individually as is known in the art. Each unitdose contains a predetermined quantity of the therapeutically activecompound sufficient to produce the desired therapeutic effect, inassociation with the required pharmaceutical carrier, vehicle ordiluent. Examples of unit dose forms include ampules and syringes andindividually packaged tablets or capsules. Unit dose forms can beadministered in fractions or multiples thereof. A multiple dose form isa plurality of identical unit dosage forms packaged in a singlecontainer to be administered in segregated unit dose form. Examples ofmultiple dose forms include vials, bottles of tablets or capsules orbottles of pints or gallons. Hence, multiple dose form is a multiple ofunit doses which are not segregated in packaging.

Sustained-release preparations can also be prepared. Suitable examplesof sustained-release preparations include semipermeable matrices ofsolid hydrophobic polymers containing the compound provided herein,which matrices are in the form of shaped articles, e.g., films, ormicrocapsule. Examples of sustained-release matrices include polyesters,hydrogels (for example, poly(2-hydroxyethyl-methacrylate), orpoly(vinylalcohol)), polylactides, copolymers of L-glutamic acid andethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradablelactic acid-glycolic acid copolymers such as the LUPRON DEPOT™(injectable microspheres composed of lactic acid-glycolic acid copolymerand leuprolide acetate), and poly-D-(−)-3-hydroxybutyric acid. Whilepolymers such as ethylene-vinyl acetate and lactic acid-glycolic acidenable release of molecules for over 100 days, certain hydrogels releaseproteins for shorter time periods. When encapsulated compounds remain inthe body for a long time, they can denature or aggregate as a result ofexposure to moisture at 37° C., resulting in a loss of biologicalactivity and possible changes in their structure. Rational strategiescan be devised for stabilization depending on the mechanism of actioninvolved. For example, if the aggregation mechanism is discovered to beintermolecular S—S bond formation through thio-disulfide interchange,stabilization can be achieved by modifying sulfhydryl residues,lyophilizing from acidic solutions, controlling moisture content, usingappropriate additives, and developing specific polymer matrixcompositions

Dosage forms or compositions containing active ingredient in the rangeof 0.001% to 100% active ingredient, 0.002% to 100% active ingredient,0.005% to 90% active ingredient, 0.01% to 100% active ingredient, 0.05%to 100% active ingredient, 0.05% to 90% active ingredient, 0.1% to 100%active ingredient, 0.1% to 1% active ingredient, 0.1% to 0.5% activeingredient, 1% to 100% active ingredient, 1% to 99% active ingredient,1% to 98% active ingredient, 1% to 97% active ingredient, 1% to 96%active ingredient, 1% to 95% active ingredient, 5% to 95% activeingredient, 10% to 100% active ingredient, 10% to 95% active ingredient,15% to 95% active ingredient, 20% to 95% active ingredient, 25% to 100%active ingredient, 50% to 100% active ingredient, 50% to 95% activeingredient, 60% to 95% active ingredient or 75% to 100% activeingredient, with the balance made up from nontoxic carrier can beprepared. For oral administration, a pharmaceutically acceptablenontoxic composition is formed by the incorporation of any of thenormally employed excipients, such as, for example pharmaceutical gradesof mannitol, lactose, starch, magnesium stearate, talcum, cellulosederivatives, sodium crosscarmellose, glucose, sucrose, magnesiumcarbonate or sodium saccharin. Such compositions include solutions,suspensions, tablets, capsules, powders and sustained releaseformulations, such as, but not limited to, implants andmicroencapsulated delivery systems, and biodegradable, biocompatiblepolymers, such as collagen, ethylene vinyl acetate, polyanhydrides,polyglycolic acid, polyorthoesters, polylactic acid and others. Methodsfor preparation of these compositions are known to those skilled in theart. The contemplated compositions can contain 0.001% to 100% activeingredient, in one embodiment or 75-95% active ingredient.

The active compounds or pharmaceutically acceptable derivatives can beprepared with carriers that protect the compound against rapidelimination from the body, such as time release formulations orcoatings.

The compositions can include other active compounds to obtain desiredcombinations of properties. The compounds provided herein, orpharmaceutically acceptable derivatives thereof as described herein, canalso be advantageously administered for therapeutic or prophylacticpurposes, to a subject having a condition modulated by one or morecaspases, together with another pharmacological agent known in thegeneral art to be of value in treating the same condition. It is to beunderstood that such combination therapy constitutes a further aspect ofthe compositions and methods of treatment provided herein.

Compositions for Oral Administration

Oral pharmaceutical dosage forms are either solid, gel or liquid. Thesolid dosage forms are tablets, capsules, granules, and bulk powders.Types of oral tablets include compressed, chewable lozenges and tabletswhich can be enteric coated, sugarcoated or film coated. Capsules can behard or soft gelatin capsules, while granules and powders can beprovided in non-effervescent or effervescent form with the combinationof other ingredients known to those skilled in the art.

In certain embodiments, the formulations are solid dosage forms, such ascapsules or tablets. The tablets, pills, capsules, troches and the likecan contain any of the following ingredients, or compounds of a similarnature: a binder; a diluent; a disintegrating agent; a lubricant; aglidant; a sweetening agent; and a flavoring agent.

Examples of binders include microcrystalline cellulose, gum tragacanth,glucose solution, acacia mucilage, gelatin solution, sucrose and starchpaste. Lubricants include talc, starch, magnesium or calcium stearate,lycopodium and stearic acid. Diluents include, for example, lactose,sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.Glidants include, but are not limited to, colloidal silicon dioxide.Disintegrating agents include crosscarmellose sodium, sodium starchglycolate, alginic acid, corn starch, potato starch, bentonite,methylcellulose, agar and carboxymethylcellulose. Coloring agentsinclude, for example, any of the approved certified water-soluble FD andC dyes, mixtures thereof; and water-insoluble FD and C dyes suspended onalumina hydrate. Sweetening agents include sucrose, lactose, mannitoland artificial sweetening agents such as saccharin, and any number ofspray dried flavors. Flavoring agents include natural flavors extractedfrom plants such as fruits and synthetic blends of compounds whichproduce a pleasant sensation, such as, but not limited to peppermint andmethyl salicylate. Wetting agents include propylene glycol monostearate,sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylenelaural ether. Emeticcoatings include fatty acids, fats, waxes, shellac,ammoniated shellac and cellulose acetate phthalates. Film coatingsinclude hydroxyethylcellulose, sodium carboxymethylcellulose,polyethylene glycol 4000 and cellulose acetate phthalate.

If oral administration is desired, the compound could be provided in acomposition that protects it from the acidic environment of the stomach.For example, the composition can be formulated in an enteric coatingthat maintains its integrity in the stomach and releases the activecompound in the intestine. The composition can also be formulated incombination with an antacid or other such ingredient.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials whichmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents. The compounds can also be administeredas a component of an elixir, suspension, syrup, wafer, sprinkle, chewinggum or the like. A syrup can contain, in addition to the activecompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors.

The active materials can also be mixed with other active materials whichdo not impair the desired action, or with materials that supplement thedesired action, such as antacids, H2 blockers, and diuretics. The activeingredient is a compound or pharmaceutically acceptable derivativethereof as described herein. Higher concentrations, up to about 98% byweight of the active ingredient can be included.

Pharmaceutically acceptable carriers included in tablets are binders,lubricants, diluents, disintegrating agents, coloring agents, flavoringagents, and wetting agents. Entericcoated tablets, because of theentericcoating, resist the action of stomach acid and dissolve ordisintegrate in the neutral or alkaline intestines. Sugarcoated tabletsare compressed tablets to which different layers of pharmaceuticallyacceptable substances are applied. Film coated tablets are compressedtablets which have been coated with a polymer or other suitable coating.Multiple compressed tablets are compressed tablets made by more than onecompression cycle utilizing the pharmaceutically acceptable substancespreviously mentioned. Coloring agents can also be used in the abovedosage forms. Flavoring and sweetening agents are used in compressedtablets, sugarcoated, multiple compressed and chewable tablets.Flavoring and sweetening agents are especially useful in the formationof chewable tablets and lozenges.

Liquid oral dosage forms include aqueous solutions, emulsions,suspensions, solutions and/or suspensions reconstituted fromnon-effervescent granules and effervescent preparations reconstitutedfrom effervescent granules. Aqueous solutions include, for example,elixirs and syrups. Emulsions are either oil in-water or water in oil.

Elixirs are clear, sweetened, hydroalcoholic preparations.Pharmaceutically acceptable carriers used in elixirs include solvents.Syrups are concentrated aqueous solutions of a sugar, for example,sucrose, and can contain a preservative. An emulsion is a two phasesystem in which one liquid is dispersed in the form of small globulesthroughout another liquid. Pharmaceutically acceptable carriers used inemulsions are non-aqueous liquids, emulsifying agents and preservatives.Suspensions use pharmaceutically acceptable suspending agents andpreservatives. Pharmaceutically acceptable substances used innon-effervescent granules, to be reconstituted into a liquid oral dosageform, include diluents, sweeteners and wetting agents. Pharmaceuticallyacceptable substances used in effervescent granules, to be reconstitutedinto a liquid oral dosage form, include organic acids and a source ofcarbon dioxide. Coloring and flavoring agents are used in all of theabove dosage forms.

Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examplesof preservatives include glycerin, methyl and propylparaben, benzoicadd, sodium benzoate and alcohol. Examples of non-aqueous liquidsutilized in emulsions include mineral oil and cottonseed oil. Examplesof emulsifying agents include gelatin, acacia, tragacanth, bentonite,and surfactants such as polyoxyethylene sorbitan monooleate. Suspendingagents include sodium carboxymethylcellulose, pectin, tragacanth, Veegumand acacia. Diluents include lactose and sucrose. Sweetening agentsinclude sucrose, syrups, glycerin and artificial sweetening agents suchas saccharin. Wetting agents include propylene glycol monostearate,sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylenelauryl ether. Organic acids include citric and tartaric acid. Sources ofcarbon dioxide include sodium bicarbonate and sodium carbonate. Coloringagents include any of the approved certified water soluble FD and Cdyes, and mixtures thereof. Flavoring agents include natural flavorsextracted from plants such fruits, and synthetic blends of compoundswhich produce a pleasant taste sensation.

For a solid dosage form, the solution or suspension, in for examplepropylene carbonate, vegetable oils or triglycerides, can beencapsulated in a gelatin capsule. Such solutions, and the preparationand encapsulation thereof, are disclosed in U.S. Pat. Nos. 4,328,245;4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g.,for example, in a polyethylene glycol, can be diluted with a sufficientquantity of a pharmaceutically acceptable liquid carrier, e.g., water,to be easily measured for administration.

Alternatively, liquid or semisolid oral formulations can be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g., propylenecarbonate) and other such carriers, and encapsulating these solutions orsuspensions in hard or soft gelatin capsule shells. Other usefulformulations include, but are not limited to, those containing acompound provided herein, a dialkylated mono- or poly-alkylene glycol,including, but not limited to, 1,2-dimethoxymethane, diglyme, triglyme,tetraglyme, polyethylene glycol-350-dimethyl ether, polyethyleneglycol-550-dimethyl ether, polyethylene glycol-750-dimethyl etherwherein 350, 550 and 750 refer to the approximate average molecularweight of the polyethylene glycol, and one or more antioxidants, such asbutylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propylgallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, thiodipropionic acid and its esters, and dithiocarbamates.

Other formulations include, but are not limited to, aqueous alcoholicsolutions including a pharmaceutically acceptable acetal. Alcohols usedin these formulations are any pharmaceutically acceptable water-misciblesolvents having one or more hydroxyl groups, including, but not limitedto, propylene glycol and ethanol. Acetals include, but are not limitedto, di(lower alkyl) acetals of lower alkyl aldehydes such asacetaldehyde diethyl acetal.

In all embodiments, tablets and capsules formulations can be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient. Thus, for example, they can becoated with a conventional enterically digestible coating, such asphenylsalicylate, waxes and cellulose acetate phthalate.

Injectables, Solutions and Emulsions

Parenteral administration, generally characterized by injection, eithersubcutaneously, intramuscularly, intravitreal, or intravenously, is alsocontemplated herein. Injectables can be prepared in conventional forms,either as liquid solutions or suspensions, solid forms suitable forsolution or suspension in liquid prior to injection, or as emulsions.Suitable excipients are, for example, water, saline, dextrose, glycerolor ethanol. In addition, if desired, the pharmaceutical compositions tobe administered can also contain minor amounts of nontoxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agents,stabilizers, solubility enhancers, and other such agents, such as forexample, sodium acetate, sorbitan monolaurate, triethanolamine oleateand cyclodextrins. Implantation of a slow release or sustained releasesystem, such that a constant level of dosage is maintained is alsocontemplated herein. Briefly, a compound provided herein is dispersed ina solid inner matrix, e.g., polymethylmethacrylate,polybutylmethacrylate, plasticized or unplasticized polyvinylchloride,plasticized nylon, plasticized polyethyleneterephthalate, naturalrubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene,ethylene-vinylacetate copolymers, silicone rubbers,polydimethylsiloxanes, silicone carbonate copolymers, hydrophilicpolymers such as hydrogels of esters of acrylic and methacrylic acid,collagen, cross-linked polyvinylalcohol and cross-linked partiallyhydrolyzed polyvinyl acetate, that is surrounded by an outer polymericmembrane, e.g., polyethylene, polypropylene, ethylene/propylenecopolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetatecopolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber,chlorinated polyethylene, polyvinylchloride, vinylchloride copolymerswith vinyl acetate, vinylidene chloride, ethylene and propylene, ionomerpolyethylene terephthalate, butyl rubber epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcoholterpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble inbody fluids. The compound diffuses through the outer polymeric membranein a release rate controlling step. The percentage of active compoundcontained in such parenteral compositions is highly dependent on thespecific nature thereof, as well as the activity of the compound and theneeds of the subject.

Parenteral administration of the compositions includes intravenous,intravitreal, subcutaneous and intramuscular administrations.Preparations for parenteral administration include sterile solutionsready for injection, sterile dry soluble products, such as lyophilizedpowders, ready to be combined with a solvent just prior to use,including hypodermic tablets, sterile suspensions ready for injection,sterile dry insoluble products ready to be combined with a vehicle justprior to use and sterile emulsions. The solutions can either be aqueousor nonaqueous.

If administered intravenously, suitable carriers include physiologicalsaline or phosphate buffered saline (PBS), and solutions containingthickening and solubilizing agents, such as glucose, polyethyleneglycol, and polypropylene glycol and mixtures thereof.

Pharmaceutically acceptable carriers used in parenteral preparationsinclude aqueous vehicles, nonaqueous vehicles, antimicrobial agents,isotonic agents, buffers, antioxidants, local anesthetics, suspendingand dispersing agents, emulsifying agents, sequestering or chelatingagents and other pharmaceutically acceptable substances.

Examples of aqueous vehicles include Sodium Chloride Injection, RingersInjection, Isotonic Dextrose Injection, Sterile Water Injection,Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehiclesinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil. Antimicrobial agents in bacteriostatic orfungistatic concentrations must be added to parenteral preparationspackaged in multiple dose containers which include phenols or cresols,mercurials, benzyl alcohol, chlorobutanol, methyl and propylphydroxybenzoic acid esters, thimerosal, benzalkonium chloride andbenzethonium chloride. Isotonic agents include sodium chloride anddextrose. Buffers include phosphate and citrate. Antioxidants includesodium bisulfate. Local anesthetics include procaine hydrochloride.Suspending and dispersing agents include sodium carboxymethylcelluose,hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifyingagents include Polysorbate 80 (TWEEN® 80). A sequestering or chelatingagent of metal ions includes EDTA. Pharmaceutical carriers also includeethyl alcohol, polyethylene glycol and propylene glycol for watermiscible vehicles and sodium hydroxide, hydrochloric acid, citric acidor lactic acid for pH adjustment.

The concentration of the pharmaceutically active compound is adjusted sothat an injection provides an effective amount to produce the desiredpharmacological effect. The exact dose depends on the age, weight andcondition of the patient or animal as is known in the art.

The unit dose parenteral preparations are packaged in an ampule, a vialor a syringe with a needle. All preparations for parenteraladministration must be sterile, as is known and practiced in the art.

Illustratively, intravenous, intravitreal, or intra-arterial infusion ofa sterile aqueous solution containing an active compound is an effectivemode of administration. Another embodiment is a sterile aqueous or oilysolution or suspension containing an active material injected asnecessary to produce the desired pharmacological effect.

Injectables are designed for local and systemic administration. Incertain embodiments, a therapeutically effective dosage is formulated tocontain a concentration of at least about 0.1% w/w up to about 90% w/wor more, or more than 1% w/w of the active compound to the treatedtissue(s). The active ingredient can be administered at once, or can bedivided into a number of smaller doses to be administered at intervalsof time. It is understood that the precise dosage and duration oftreatment is a function of the tissue being treated and can bedetermined empirically using known testing protocols or by extrapolationfrom in vivo or in vitro test data. It is to be noted thatconcentrations and dosage values also can vary with the age of theindividual treated. It is to be further understood that for anyparticular subject, specific dosage regimens can be adjusted over timeaccording to the individual need and the professional judgment of theperson administering or supervising the administration of theformulations, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed formulations.

The compound can be suspended in micronized or other suitable form orcan be derivatized to produce a more soluble active product or toproduce a prodrug. The form of the resulting mixture depends upon anumber of factors, including the intended mode of administration and thesolubility of the compound in the selected carrier or vehicle. Theeffective concentration is sufficient for ameliorating the symptoms ofthe condition and can be empirically determined.

Lyophilized Powders

Of interest herein are also lyophilized powders, which can bereconstituted for administration as solutions, emulsions and othermixtures. They also can be reconstituted and formulated as solids orgels.

The sterile, lyophilized powder is prepared by dissolving a compoundprovided herein, or a pharmaceutically acceptable derivative thereof, ina suitable solvent. The solvent can contain an excipient which improvesthe stability or other pharmacological component of the powder orreconstituted solution, prepared from the powder. Excipients that can beused include, but are not limited to, dextrose, sorbital, fructose, cornsyrup, xylitol, glycerin, glucose, sucrose or other suitable agent. Thesolvent can also contain a buffer, such as citrate, sodium or potassiumphosphate or other such buffer known to those of skill in the art atabout neutral pH. Subsequent sterile filtration of the solution followedby lyophilization under standard conditions known to those of skill inthe art provides the desired formulation. Generally, the resultingsolution will be apportioned into vials for lyophilization. Each vialwill contain a single dosage (10-1000 mg or 100-500 mg) or multipledosages of the compound. The lyophilized powder can be stored underappropriate conditions, such as at about 4 degrees Celsius to roomtemperature.

Reconstitution of this lyophilized powder with water for injectionprovides a formulation for use in parenteral administration. Forreconstitution, about 1-50 mg, 5-35 mg or about 9-30 mg of lyophilizedpowder, is added per mL of sterile water or other suitable carrier. Theprecise amount depends upon the selected compound. Such amount can beempirically determined. Topical administration Topical mixtures areprepared as described for the local and systemic administration. Theresulting mixture can be a solution, suspension, emulsions or the likeand are formulated as creams, gels, ointments, emulsions, solutions,elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols,irrigations, sprays, suppositories, bandages, dermal patches, contactlens or any other formulations suitable for topical administration.

The compounds or pharmaceutically acceptable derivatives thereof can beformulated as aerosols for topical application, such as by inhalation(see, e.g., U.S. Pat. Nos. 4,044,126, 4,414,209, and 4,364,923, whichdescribe aerosols for delivery of a steroid useful for treatment ofinflammatory diseases, particularly asthma). These formulations foradministration to the respiratory tract can be in the form of an aerosolor solution for a nebulizer, or as a microfine powder for insufflation,alone or in combination with an inert carrier such as lactose. In such acase, the particles of the formulation will have diameters of less than50 microns or less than 10 microns.

The compounds can be formulated for local or topical application, suchas for topical application to the skin and mucous membranes, such as inthe eye, in the form of gels, creams, and lotions and for application tothe eye or for intracisternal or intraspinal application. Topicaladministration is contemplated for transdermal delivery and also foradministration to the eyes or mucosa, or for inhalation therapies. Nasalsolutions of the active compound alone or in combination with otherpharmaceutically acceptable excipients can also be administered.

These solutions, particularly those intended for ophthalmic use, can beformulated as 0.01%-10% isotonic solutions, pH about 5-7, withappropriate salts.

Compositions for Other Routes of Administration

Other routes of administration, such as topical application, transdermalpatches, and rectal administration are also contemplated herein.

For example, pharmaceutical dosage forms for rectal administration arerectal suppositories, capsules and tablets for systemic effect. Rectalsuppositories are used herein mean solid bodies for insertion into therectum which melt or soften at body temperature releasing one or morepharmacologically or therapeutically active ingredients.Pharmaceutically acceptable substances utilized in rectal suppositoriesare bases or vehicles and agents to raise the melting point. Examples ofbases include cocoa butter (theobroma oil), glycerin gelatin, carbowax(polyoxyethylene glycol) and appropriate mixtures of mono, di andtriglycerides of fatty acids. Combinations of the various bases can beused. Agents to raise the melting point of suppositories includespermaceti and wax. Rectal suppositories can be prepared either by thecompressed method or by molding. In certain embodiments, the weight of arectal suppository is about 2 to 3 gm.

Tablets and capsules for rectal administration are manufactured usingthe same pharmaceutically acceptable substance and by the same methodsas for formulations for oral administration.

Sustained Release Compositions

Active ingredients such as the compounds provided herein can beadministered by controlled release means or by delivery devices that arewell known to those of ordinary skill in the art. Examples include, butare not limited to, those described in U.S. Pat. Nos. 3,845,770;3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595;5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480;5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945;5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363;6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358 and6,699,500 each of which is incorporated herein by reference. Such dosageforms can be used to provide slow or controlled release of one or moreactive ingredients using, for example, hydropropylmethyl cellulose,other polymer matrices, gels, permeable membranes, osmotic systems,multilayer coatings, microparticles, liposomes, microspheres, or acombination thereof to provide the desired release profile in varyingproportions. Suitable controlled release formulations known to those ofordinary skill in the art, including those described herein, can bereadily selected for use with the active ingredients provided herein.Thus, the compositions provided encompass single unit dosage formssuitable for oral administration such as, but not limited to, tablets,capsules, gel caps, and caplets that are adapted for controlled release.

All controlled release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designed controlledrelease preparation in medical treatment is characterized by a minimumof drug substance being employed to cure or control the condition in aminimum amount of time. Advantages of controlled release formulationsinclude extended activity of the drug, reduced dosage frequency, andincreased subject compliance. In addition, controlled releaseformulations can be used to affect the time of onset of action or othercharacteristics, such as blood levels of the drug, and can thus affectthe occurrence of side (e.g., adverse) effects.

Most controlled release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

In certain embodiments, the drug can be administered using intravenousinfusion, an implantable osmotic pump, a transdermal patch, liposomes,or other modes of administration. In one embodiment, a pump can be used(see, Sefton, CRC Crit. Ref Biomed. Eng. 1987; 14:201, Buchwald et al.,Surgery 1980; 88:507, Saudek et al., N. Engl. J. Med. 1989; 321: 574. Inanother embodiment, polymeric materials can be used. In yet anotherembodiment, a controlled release system can be placed in a subject at anappropriate site determined by a practitioner of skill, i.e., thusrequiring only a fraction of the systemic dose (see, e.g., Goodson,Medical Applications of Controlled Release, vol. 2, 1984, pp. 115-138.Other controlled release systems are discussed in the review by Langer(Science 1990; 249:1527-1533. The active ingredient can be dispersed ina solid inner matrix, e.g., polymethylmethacrylate,polybutylmethacrylate, plasticized or unplasticized polyvinylchloride,plasticized nylon, plasticized polyethyleneterephthalate, naturalrubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene,ethylene-vinylacetate copolymers, silicone rubbers,polydimethylsiloxanes, silicone carbonate copolymers, hydrophilicpolymers such as hydrogels of esters of acrylic and methacrylic acid,collagen, cross-linked polyvinylalcohol and cross-linked partiallyhydrolyzed polyvinyl acetate, that is surrounded by an outer polymericmembrane, e.g., polyethylene, polypropylene, ethylene/propylenecopolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetatecopolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber,chlorinated polyethylene, polyvinylchloride, vinylchloride copolymerswith vinyl acetate, vinylidene chloride, ethylene and propylene, ionomerpolyethylene terephthalate, butyl rubber epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcoholterpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble inbody fluids. The active ingredient then diffuses through the outerpolymeric membrane in a release rate controlling step. The percentage ofactive ingredient in such parenteral compositions is highly dependent onthe specific nature thereof, as well as the needs of the subject.

Targeted Formulations

The compounds provided herein, or pharmaceutically acceptablederivatives thereof, can also be formulated to be targeted to aparticular tissue, receptor, or other area of the body of the subject tobe treated. Many such targeting methods are well known to those of skillin the art. All such targeting methods are contemplated herein for usein the instant compositions. For non-limiting examples of targetingmethods, see, e.g., U.S. Pat. Nos. 6,316,652, 6,274,552, 6,271,359,6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082,6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252,5,840,674, 5,759,542 and 5,709,874.

In one embodiment, liposomal suspensions, including tissue-targetedliposomes, such as tumor-targeted liposomes, can also be suitable aspharmaceutically acceptable carriers. These can be prepared according tomethods known to those skilled in the art. For example, liposomeformulations can be prepared as described in U.S. Pat. No. 4,522,811.Briefly, liposomes such as multilamellar vesicles (MLV's) can be formedby drying down egg phosphatidyl choline and brain phosphatidyl serine(7:3 molar ratio) on the inside of a flask. A solution of a compoundprovided herein in phosphate buffered saline lacking divalent cations(PBS) is added and the flask shaken until the lipid film is dispersed.The resulting vesicles are washed to remove unencapsulated compound,pelleted by centrifugation, and then resuspended in PBS.

Dosage and Unit Dosage Forms

In human therapeutics, the doctor will determine the posology which heconsiders most appropriate according to a preventive or curativetreatment and according to the age, weight, stage of the disease andother factors specific to the subject to be treated. Generally, dosesare from about 1 to about 1000 mg per day for an adult, or from about 5to about 250 mg per day or from about 10 to 50 mg per day for an adult.In certain embodiments, doses are from about 5 to about 400 mg per dayor 25 to 200 mg per day per adult. Dose rates of from about 50 to about500 mg per day are also contemplated.

In certain embodiments, the amount of the compound or composition whichwill be effective in the treatment of colon cancer or prevention one ormore symptoms thereof will vary with the nature and severity of thedisease or condition, and the route by which the active ingredient isadministered. The frequency and dosage will also vary according tofactors specific for each subject depending on the specific therapy(e.g., therapeutic or prophylactic agents) administered, the severity ofthe disorder, disease, or condition, the route of administration, aswell as age, body, weight, response, and the past medical history of thesubject. Effective doses can be extrapolated from dose-response curvesderived from in vitro or animal model test systems.

Exemplary doses of a composition include milligram or microgram amountsof the chemotherapeutic agent and caspase inhibitor per kilogram ofsubject or sample weight (e.g., about 0.001-1000 mg/Kg, about 0.01-100mg/Kg, about 0.01-50 mg/Kg, about 0.1-25 mg/Kg, or about 0.1-10 mg/Kg.In certain embodiments, the dosage administered to a subject is between0.20 mg/kg and 2.00 mg/kg, or between 0.30 mg/kg and 1.50 mg/kg of thesubject's body weight.

In certain embodiments, the recommended daily dose range of the caspaseinhibitors described herein and, optionally, where applicable, aco-administered chemotherapeutic agent, for the conditions describedherein, lies within the range of from about 0.1 mg to about 1000 mg ofeach of the chemotherapeutic agent and caspase inhibitor per day, givenas a single once-a-day dose or as divided doses throughout a day. In oneembodiment, the daily dose is administered twice daily in equallydivided doses. Specifically, a daily dose range should be from about 10mg to about 200 mg per day, more specifically, between about 10 mg andabout 150 mg per day, or even more specifically between about 25 andabout 100 mg per day. It sometimes is necessary to use dosages of theactive ingredient outside the ranges disclosed herein in some cases, aswill be apparent to those of ordinary skill in the art. Furthermore, itis noted that the clinician or treating physician will know how and whento interrupt, adjust, or terminate therapy in conjunction with subjectresponse.

Different therapeutically effective amounts can be applicable fordifferent diseases and conditions, as will be readily known by those ofordinary skill in the art. Similarly, amounts sufficient to prevent,manage, treat or ameliorate such disorders, but insufficient to cause,or sufficient to reduce, adverse effects associated with the compounddescribed herein are also encompassed by the above described dosageamounts and dose frequency schedules. Further, when a subject isadministered multiple dosages of a compound described herein, not all ofthe dosages need be the same. For example, the dosage administered tothe subject can be increased to improve the prophylactic or therapeuticeffect of the compound or it can be decreased to reduce one or more sideeffects that a particular subject is experiencing.

In one embodiment, the dosage of compounds described herein administeredto prevent, treat, manage, or ameliorate a disorder, or one or moresymptoms thereof in a subject is 0.1 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4mg/kg, 5 mg/kg, 6 mg/kg, 10 mg/kg, or 15 mg/kg or more of a subject'sbody weight. In another embodiment, the dosage of the compounds providedherein administered to prevent, treat, manage, or ameliorate a disorder,or one or more symptoms thereof in a subject is a unit dose of 0.1 mg to200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5 mg, 0.1 mg to 5 mg,0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to10 mg, 0.25 mg to 7.5 mg, 0.25 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 7.5 mg, 1 mg to5 mg, or 1 mg to 2.5 mg.

In certain embodiments, treatment or prevention can be initiated withone or more loading doses of the caspase inhibitor and, optionally,where applicable, a co-administered chemotherapeutic agent, followed byone or more maintenance doses. In such embodiments, the loading dose canbe, for instance, about 60 to about 400 mg per day, or about 100 toabout 200 mg per day for one day to five weeks. The loading dose can befollowed by one or more maintenance doses. Each maintenance does can be,independently, about from about 10 mg to about 200 mg per day, morespecifically, between about 25 mg and about 150 mg per day, or even morespecifically between about 25 mg and about 80 mg per day or betweenabout 25 mg and about 50 mg per day. Maintenance doses can beadministered daily and can be administered as single doses, or asdivided doses.

In certain embodiments, a dose of the caspase inhibitor and, optionally,where applicable, a co-administered chemotherapeutic agent, can beadministered to achieve a steady-state concentration of the activeingredient in blood or serum of the subject. The steady-stateconcentration can be determined by measurement according to techniquesavailable to those of skill or can be based on the physicalcharacteristics of the subject such as height, weight and age. Incertain embodiments, a sufficient amount of a compound provided hereinis administered to achieve a steady-state concentration in blood orserum of the subject of from about 300 to about 4000 ng/mL, from about400 to about 1600 ng/mL, or from about 600 to about 1200 ng/mL. Loadingdoses can be administered to achieve steady-state blood or serumconcentrations of about 1200 to about 8000 ng/mL, or about 2000 to about4000 ng/mL for one to five days. Maintenance doses can be administeredto achieve a steady-state concentration in blood or serum of the subjectof from about 300 to about 4000 ng/mL, from about 400 to about 1600ng/mL, or from about 600 to about 1200 ng/mL.

In certain embodiments, administration of the same compound can berepeated and the administrations can be separated by at least 1 day, 2days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75days, 3 months, or 6 months. In other embodiments, administration of thesame prophylactic or therapeutic agent can be repeated and theadministration can be separated by at least at least 1 day, 2 days, 3days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3months, or 6 months.

In certain aspects, provided herein are unit dosages comprising acompound, or a pharmaceutically acceptable derivative thereof, in a formsuitable for administration. Such forms are described in detail above.In certain embodiments, the unit dosage comprises 1 to 1000 mg, 5 to 250mg or 10 to 50 mg active ingredient. In particular embodiments, the unitdosages comprise about 1, 5, 10, 25, 50, 100, 125, 250, 500 or 1000 mgactive ingredient. Such unit dosages can be prepared according totechniques familiar to those of skill in the art.

6.5. Articles of Manufacture

The compounds or pharmaceutically acceptable derivatives can be packagedas articles of manufacture containing packaging material, a compound orpharmaceutically acceptable derivative thereof provided herein, which isused for treatment, prevention or amelioration of a condition modulationby caspases or one or more symptoms associated with the condition, and alabel that indicates that the compound or pharmaceutically acceptablederivative thereof is used for treatment, prevention or amelioration ofthe condition or one or more symptoms of the condition.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical products arewell known to those of skill in the art. See, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packagingmaterials include, but are not limited to, blister packs, bottles,tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, andany packaging material suitable for a selected formulation and intendedmode of administration and treatment. A wide array of formulations ofthe compounds and compositions provided herein are contemplated.

6.6. Kits

Further provided are kits for use of the compounds provided herein inmethods of treatment. The kits can include a caspase inhibitor orcomposition thereof, and instructions providing information to a healthcare provider regarding usage for treating or preventing a conditionmodulated by one or more caspases. Instructions can be provided inprinted form or in the form of an electronic medium such as a CD, orDVD, or in the form of a website address where such instructions can beobtained. A unit dose of a caspase inhibitor or composition thereof, caninclude a dosage such that when administered to a subject, atherapeutically or prophylactically effective plasma level of thecompound or composition can be maintained in the subject for at least 1day. In some embodiments, the compounds or composition can be includedas sterile aqueous pharmaceutical compositions or dry powder (e.g.,lyophilized) compositions.

6.7. Schematics for the Preparation of Compounds

The compounds provided herein can be prepared by the general processesoutlined in the schemes below. In schemes 1-4, where Ar and Ar′ are eacharyl, and R¹, R², R³, Y¹, Y² and Y³ are selected as described elsewhereherein.

where M=lower alkylene, OR^(m) or NR^(n)R^(o), where R^(m) is optionallysubstituted aryl or optionally substituted heteroaryl, R^(n) and R^(o)are each independently hydrogen, optionally substituted alkyl,optionally substituted aryl or optionally substituted heteroaryl, orR^(n) and R^(o) together with the nitrogen atom on which they aresubstituted form a heterocyclic or heteroaryl ring, each of which isoptionally substituted.

The following examples present certain exemplary embodiments and areintended by way of illustration and not by way of limitation.

7. EXAMPLES

The following Examples are presented by way of illustration, notlimitation. One skilled in the art can modify the procedures set forthin the illustrative examples to arrive at the desired products.

Example 1

Ethyl 2-((2,6-difluorophenyl)amino)-2-oxoacetate (3): Triethylamine(27.2 mL, 193.8 mmol, 1 equiv.) was added to a solution of2,6-difluoroaniline (25.0 g, 193.8 mmol, 1 equiv.) in THF (1 L) at 0-5°C. Ethyl oxalyl chloride (21.6 mL, 193.8 mmol, 1 equiv.) was addeddropwise over 60 minutes, while maintaining the temperature <5° C. Thereaction was warmed to room temperature and stirred for 24 hours. Thereaction was filtered through celite, the celite was washed with methylt-butyl ether (500 mL) and the combined organic layers were washed witha 1N HCl (2×200 mL) and water (400 mL). The organic layer was dried oversodium sulfate, filtered and concentrated under reduced pressure to givethe desired product as a beige oil (44.8 g, quantitative yield).

2-((2,6-Difluorophenyl)amino)-2-oxoacetic acid (4): 1N Lithium hydroxide(233 mL, 233 mmol, 1.2 equiv.) was added to a solution of compound 3(44.8 g, 193.8 mmol, 1 equiv.) in THF (233 mL). After stirring at roomtemperature for 4 hours, the reaction was cooled to 0° C. and acidifiedwith concentrated HCl to pH 2. The aqueous mix was saturated with sodiumchloride and extracted with ethyl acetate (6×200 mL). The combinedorganic layers were dried over sodium sulfate, filtered and concentratedunder reduced pressure to give the desired product as a white solid(18.3 g, 47% yield).

Ethyl (2-((2,6-difluorophenyl)amino)-2-oxoacetyl)-L-alaninate (7):EDC.HCl (25.9 g, 135 mmol, 1.4 equiv.) was added to a suspension ofcompound 4 (19.4 g, 96.5 mmol, 1.0 equiv.), HOAt (18.4 g, 135 mmol, 1.4equiv.) in acetonitrile (1.0 L). The mixture was stirred at roomtemperature until all solids dissolved. L-Alanine ethyl esterhydrochloride (14.8 g, 96.5 mmol, 1.0 equiv.) and N-methylmorpholine(19.5 g, 193 mmol, 2.0 equiv) were added and the mixture was stirred atroom temperature overnight. LC-MS analysis indicated that the reactionwas complete. The mixture was concentrated under reduced pressure, andthe wet solid was diluted in ethyl acetate (300 mL) and water (100 mL).The layers were separated, and the aqueous layer was extracted withethyl acetate (2×50 mL). The combined organic layers were washed withsaturated brine (50 mL), dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was dissolved indichloromethane (200 mL) and absorbed onto Celite (30 g). Purificationon an Interchim automated system (330 g column) eluting with a gradientof 0 to 5% ethyl acetate in dichloromethane gave compound 7 (18.2 g,62.8% yield) as a white solid.

(2-((2,6-Difluorophenyl)amino)-2-oxoacetyl)-L-alanine (8): 1N Lithiumhydroxide (1.0 N, 71.5 mL, 71.5 mmol, 1.2 equiv.) was added to asolution of compound 7 (17.9 g, 59.6 mmol, 1.0 equiv.) intetrahydrofuran (240 mL) at room temperature. After stirring for 48hours, LC-MS analysis indicated that the reaction was complete. Themixture was cooled in an ice water bath and adjusted with concentratedHCl to pH=2. Saturated brine (300 mL) was added and the layers wereseparated. The aqueous layer was extracted with ethyl acetate (50 mL).The combined organic layers were dried over sodium sulfate, filtered andconcentrated. The wet solid was mixed with 25% ethyl acetate in toluene(400 mL) at 40° C. for 30 minutes, concentrated under reduced pressureand dried under vacuum at 40° C. overnight to give compound 8 (14.1 g,86.9% yield) as a white solid.

tert-Butyl 2-(7-chloro-1-oxoisoquinolin-2(1H)-yl)acetate (Compound 14B):A mixture of 7-chloroisoquinolin-1-ol (18 g, 100.2 mmol, 1.0 equiv.),cesium carbonate (65.3 g, 200 mmol, 2.0 equiv.) and t-butyl bromoacetate(29.3 g, 22 mL, 150 mmol, 1.5 equiv.) in dimethylformamide (500 mL) wasstirred at 80° C. for 24 hours. The solvent was removed under reducedpressure and the residue was diluted with ethyl acetate (1000 mL) andwashed with water (3×300 mL). The organic layer was dried over sodiumsulfate, filtered and concentrated under reduced pressure. The resultingoil was dissolved in dichloromethane (500 mL) and absorbed onto silicagel (100 g). The material was divided into four equal portions. Eachportion was purified on an Interchim HPLC system (330 g silica gelcolumn), eluting with a gradient of 0 to 50% ethyl acetate in heptanesto give the desired product (25.8 g, 88% yield) as a white solid.

2-(7-Chloro-1-oxoisoquinolin-2(1H)-yl)acetic acid (Compound 15): Amixture of compound 14B (14.3 g, 49.1 mmol) and trifluoroacetic acid(27.9 g, 18.8 mL, 245 mmol, 5.0 equiv.) in dichloromethane (300 mL) wasstirred for 48 hours at room temperature. The solvent was removed underreduced pressure. The resulting solid was triturated with methyl t-butylether (500 mL), suction-filtered and washed with methyl t-butyl ether(3×200 mL). The solid was dried under vacuum at room temperatureovernight to give the desired product (8.1 g, 69% yield) as a whitesolid.

tert-Butyl (S)-(5-(benzyloxy)-1-bromo-2-oxopentan-3-yl)carbamate (19-3):Isobutyl chloroformate (6.59 mL, 50.8 mmol, 1.5 equiv.) was addeddropwise to a solution of Boc-O-benzyl-L-homoserine (19-1) (10.5 g, 33.9mmol, 1 equiv.) and N-methylmorpholine (5.96 mL, 54.2 mmol, 1.6 equiv.)in THF (113 mL) at −10° C. After stirring at −10° C. for 20 minutes, thereaction was filtered through celite and concentrated under reducedpressure to give the mixed anhydride (13.9 g) as a colorless oil, whichwas used subsequently.

Diazomethane preparation: A solution ofN-methyl-N′-nitroso-p-toluenesulfonamide (Diazald®, 21.8 g, 101.6 mmol,1 equiv.) in diethyl ether (113 mL) was added through an addition funnelto a mixture of potassium hydroxide (17.1 g, 304.8 mmol, 3 equiv.) inethanol (34 mL) and water (27 mL) in an oil bath at 65° C. The receivingflask to collect the ethereal solution of diazomethane was cooled in anice-bath and the Diazald® solution was added at such a rate as thatallowed for a dropwise distillation into the receiving flask. When allof the Diazald® solution had been added, additional diethyl ether (10mL) was added through the addition funnel until the distillate was clear(no remaining diazomethane). After cooling to room temperature, themixture in the distillation flask was quenched slowly with acetic aciduntil the yellow color disappeared.

A solution of freshly prepared mixed anhydride above (13.9 g, 33.9 mmol,1 equiv.) in diethyl ether (75 mL) was placed in a clear-seal jointflask and cooled to 0° C. in an ice bath. The freshly prepareddiazomethane ethereal solution (˜101.6 mmol, 3 equiv.) was added throughan addition funnel dropwise while keeping it cold. The resulting mixturewas stirred at 0° C. for 15 minutes, warmed to room temperature andstirred for 30 minutes. The reaction was cooled to 0° C. Meanwhile amixture of 48% aqueous HBr (26.8 mL, 237 mmol, 7 equiv.) and acetic acid(26.8 mL) was cooled to 0° C. and added to the above reaction mixtureslowly at 0° C. The mixture was stirred at 0° C. for 15 minutes, warmedto room temperature and stirred for 30 minutes. The mixture was dilutedwith diethyl ether (100 mL), washed with water (3×100 mL), dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified on an InterChim auto-chromatography system (220 gSorbTech silica gel column), eluting with a gradient of 0 to 40% ethylacetate in heptanes to give compound 19-3 (9.0 g, 73% yield) as acolorless oil.

tert-Butyl(S)-(5-(benzyloxy)-2-oxo-1-(2,3,5,6-tetrafluorophenoxy)pentan-3-yl)carbamate(19-4): Potassium fluoride (5.46 g, 94.0 mmol, 4 equiv.) was added to asolution of compound 19-3 (9.0 g, 23.5 mmol, 1 equiv.) and2,3,5,6-tetrafluorophenol (4.29 g, 28.8 mmol, 1.1 equiv.) in DMF (120mL). After stirring at room temperature for 16 hours, the reaction wasdiluted with ethyl acetate (100 mL), washed with saturated sodiumbicarbonate (100 mL) and saturated brine (100 mL). The organic layer wasdried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified on an InterChim auto-chromatographysystem (220 g SorbTech silica gel column), eluting with a gradient of 10to 40% ethyl acetate in heptanes to give compound 19-4 (5.40 g, 49%yield) as a colorless oil.

(S)-3-Amino-5-(benzyloxy)-1-(2,3,5,6-tetrafluorophenoxy)pentan-2-onehydrochloride (19-5): 4M HCl in 1,4-dioxane (3.5 mL, 13.8 mmol, 1.2equiv.) was added dropwise to a solution of compound 19-4 (5.40 g, 11.5mmol, 1 equiv.) in acetonitrile (60 mL) at 5° C. The mixture was thenwarmed to room temperature and stirred overnight. LCMS indicated thatthe reaction was not complete. Additional 4M HCl in 1,4-dioxane (2.30mL, 9.2 mmol, 0.8 equiv.) was added and the mixture was stirred for 6hours at which time LCMS indicated that the reaction was complete. Themixture was concentrated under reduced pressure to give compound 19-5(4.0 g, 86% yield) as a light yellow solid.

N¹—((S)-1-(((S)-5-(Benzyloxy)-2-oxo-1-(2,3,5,6-tetrafluorophenoxy)pentan-3-yl)amino)-1-oxopropan-2-yl)-N²-(2,6-difluorophenyl)oxalamide(19-6, Example 1): EDC.HCl (0.907 g, 4.73 mmol, 1.1 equiv.) was added toa suspension of compound 8 (1.17 g, 4.30 mmol, 1.0 equiv.) and HOAt(0.702 g, 5.16 mmol, 1.2 equiv.) in acetonitrile (20 mL). The mixturewas stirred at room temperature until all solids dissolved. Compound19-5 (1.75 g, 4.30 mmol, 1.0 equiv.) and triethylamine (1.20 mL, 8.6mmol, 2.0 equiv.) were added and the mixture was stirred at roomtemperature overnight. LC-MS analysis indicated that the reaction wascomplete. The mixture was diluted with ethyl acetate (40 mL) and washedwith saturated sodium bicarbonate (30 mL) and saturated brine (30 mL).The organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was purified onan Interchim automated system (40 g column), eluting with a gradient of10 to 70% ethyl acetate in heptanes to give compound 19-6, (Example 1)(1.90 g, 71% yield) as a light yellow solid, (Mass Spec. m/z=626.1(M+H).

Example 2

N¹—(2,6-Difluorophenyl)-N²—((S)-1-(((S)-5-hydroxy-2-oxo-1-(2,3,5,6-tetrafluorophenoxy)pentan-3-yl)amino)-1-oxopropan-2-yl)oxalamide(19-7, Example 2): A mixture of compound (1.30 g, 2.08 mmol, 1.0 equiv.)and 10% palladium on activated carbon (130 mg, 50% wet) intetrahydrofuran (18 mL) and methanol (18 mL) was hydrogenated @ 45 psifor 3 hours. LC-MS analysis indicated that the reaction was complete.The mixture was filtered through Celite (20 g), which was washed withadditional methanol (25 mL). The crude product was purified twice on anInterchim automated system. Two 40 g columns were used for purification.The first purification was done on a 40 g silica gel column, elutingwith a gradient of 0 to 10% methanol in dichloromethane. The materialwas then further purified on a second 40 g silica gel column, elutingwith a gradient of 30 to 90% ethyl acetate in heptanes. The product wasdissolved in diethyl ether (3 mL) and precipitated by the addition ofheptanes (5 mL). The solid was dried on the filter to give the desiredproduct. The product was purified on an Interchim automated system(Teledyne ISCO Column Gold C18 50G column), eluting with a gradient of 0to 50% acetonitrile in water to give compound 19-7, (Example 2) (325 mg,29% yield) as a white solid, (Mass Spec. m/z=536 (M+H).

Example 3

N-(tert-Butoxycarbonyl)-O-(4-chlorobenzyl)-L-homoserine (42-2a): A 60%dispersion of sodium hydride in mineral oil (6.02 g, 150.5 mmol, 2.2equiv.) was added to a solution of compound 42-1 (15.0 g, 68.4 mmol, 1equiv.) in anhydrous N,N-dimethylacetamide (100.0 mL) at 0° C. Afterstirring 1.5 hours at 0° C., 4-chlorobenzyl bromide (15.465 g, 75.3mmol, 1.1 equiv.) was added and\the reaction was stirred at roomtemperature for 16 hours. The reaction mixture was diluted with ice-coldwater (200 mL) and extracted with diethyl ether (2×800 mL). The aqueouslayer was acidified to pH 3.4 with 3M HCl (30 mL) and extracted withethyl acetate (1 L). The organic layer was washed with saturated brinesolution (1 L) and water (3×1 L), dried over sodium sulfate (150 g) andconcentrated under reduced pressure. The crude material was absorbed onto celite (30 g) and purified on an Interchim automated chromatographysystem (Sorbtech silica gel column, 330 g), eluting with a gradient of 0to 10% methanol in dichloromethane to give compound 42-2a (3.9 g, 16%yield) as a viscous pale yellow oil.

Methyl N-(tert-butoxycarbonyl)-O-(4-chlorobenzyl)-L-homoserinate(42-3a): Potassium carbonate (1.369 g, 9.9 mmol, 2.0 equiv.) was addedto solution of compound 42-2a (1.7 g, 4.9 mmol, 1.0 equiv.) in DMF (10mL). After stirring at room temperature for 10 minutes, methyl iodide(0.617 mL, 9.9 mmol, 2.0 equiv.) was added and the reaction was stirredat room temperature for 16 hours. The reaction mixture was diluted withethyl acetate (500 mL) and washed with saturated brine solution (3×500mL) and water (500 mL). The organic layer was dried over sodium sulfate(100 g) and concentrated under reduced pressure. The crude material wasabsorbed on to celite (4 g) and purified on an Interchim automatedchromatography system (Sorbtech silica gel column, 80 g), eluting with agradient of 0 to 60% ethyl acetate in heptanes to give compound 42-3a(1.4 g, 78% yield) as a colorless oil.

tert-Butyl(S)-(1-chloro-5-((4-chlorobenzyl)oxy)-2-oxopentan-3-yl)carbamate(42-4a): 1.6 M, n-BuLi in hexane (12.224 mL, 19.5 mmol, 5.0 equiv.) wasadded to diisopropylamine (3.0 mL, 21.5 mmol, 5.5 equiv.) in THF (20 mL)at −78° C. The reaction was warmed to 0° C. for 5 minutes, cooled to−78° C. and slowly added over 45 minutes to compound 42-3a (1.4 g, 3.9mmol, 1.0 equiv.) in THF (20 mL) at −78° while maintaining thetemperature <−72° C. After stirring at −78° C. for 45 minutes, aceticacid (9 mL) was added drop wise at −78° C. The reaction was diluted withsaturated brine solution (800 mL) and extracted with ethyl acetate (500mL). The organic layer was washed with saturated bicarbonate (3×500 mL)and water (250 mL). The ethyl acetate layer was dried over sodiumsulfate (100 g) and concentrated under reduced pressure. The crudematerial was absorbed on to celite (6 g) and purified on an Interchimautomated chromatography system (Sorbtech silica gel column, 80 g),eluting with a gradient of 0 to 40% ethyl acetate in heptanes to givecompound 42-4a (1.0 g, 67% yield) as a light yellow oil.

Potassium salt of 2,3,5,6-tetrafluorophenol: 2,3,5,6-tetrafluorophenol(2.0 g, 12.0 mmol, 1.0 equiv.) was added to a solution of potassiumhydroxide (0.68 g, 12.0 mmol, 1.0 equiv.) in methanol. After stirring atroom temperature for 18 hours, the solvents were removed under reducedpressure. The residue was dried under vacuum at room temperature for 16hours to give the potassium salt of 2,3,5,6-tetrafluorophenol (2.4 g,97% yield) as white solid.

tert-Butyl(S)-(5-((4-chlorobenzyl)oxy)-2-oxo-1-(2,3,5,6-tetrafluorophenoxy)pentan-3-yl)carbamate (42-5a): Sodium iodide (0.6 g, 4.0 mmol, 1.5equiv.) and the potassium salt of 2,3,5,6-tetrafluorophenol (0.813 g,4.0 mmol, 1.5 equiv.) were added to a solution of compound 42-4a (1.0 g,2.6 mmol, 1.0 equiv.) in acetone (12 mL). After stirring at roomtemperature for 20 hours, the solvents were removed under reducedpressure. The residue was diluted with ethyl acetate (500 mL) and washedwith saturated brine (250 mL). The organic layer was dried over sodiumsulfate, filtered and concentrated under reduced pressure. The crudematerial was absorbed on to celite (4 g) and purified on an Interchimautomated chromatography system (Sorbtech silica gel column, 80 g),eluting with a gradient of 0 to 40% ethyl acetate in heptanes to givecompound 42-5a (0.89 g, 66% yield) as a light yellow oil.

(S)-3-Amino-5-((4-chlorobenzyl)oxy)-1-(2,3,5,6-tetrafluorophenoxy)pentan-2-onehydrogen chloride (42-6a): 4M HCl in 1,4-dioxane (0.869 mL, 3.5 mmol,2.0 equiv.) was added dropwise to a solution of compound 42-5a (0.885 g,1.7 mmol, 1 equiv.) in acetonitrile (15 mL) at 5° C. The mixture waswarmed to room temperature and stirred for 24 hours. The mixture wasconcentrated under reduced pressure. The residue was triturated withheptanes (3×10 mL) and decanted and dried under vacuum to give compound42-6a (0.633 g, 81% yield) as an off-white solid.

N¹—((S)-1-(((S)-5-((4-Chlorobenzyl)oxy)-2-oxo-1-(2,3,5,6-tetrafluorophenoxy)pentan-3-yl)amino)-1-oxopropan-2-yl)-N²—(2,6-difluorophenyl)oxalamide(42-A, Example 3):

EDC.HCl (0.286 g, 1.5 mmol, 1.1 equiv.) was added to a suspension ofcompound 8 (0.369 g, 1.4 mmol, 1.0 equiv.) and HOAt (0.221 g, 1.6 mmol,1.2 equiv.) in acetonitrile (10 mL). The mixture was stirred at roomtemperature until all solids dissolved. Compound 42-6a (0.6 g, 1.4 mmol,1.0 equiv.) and triethylamine (0.378 mL, 2.7 mmol, 2.0 equiv.) weresequentially added and the mixture was stirred at room temperature for20 hours. The mixture was diluted with ethyl acetate (250 mL) and washedwith saturated sodium bicarbonate (250 mL) and saturated brine (250 mL).The organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude material was absorbed onto celite (4 g) and purified on an Interchim automated chromatographysystem (Sorbtech silica gel column, 80 g), eluting with a gradient of 0to 60% ethyl acetate in heptanes to give 42-A, (Example 3) (0.59 g, 65%yield) as a white solid, (Mass Spec. m/z=660.1 (M+H).

N-(tert-Butoxycarbonyl)-O-(thiophen-3-ylmethyl)-L-homoserine (42-2d): A60% dispersion of sodium hydride in mineral oil (4.29 g, 107.3 mmol, 2.2equiv.) was added to a solution of compound 42-1 (10.69 g, 48.78 mmol, 1equiv.) in anhydrous N,N-dimethylacetamide (80.0 mL) at 0° C. Afterstirring for 1.5 hours at 0° C., 3-bromomethylthiophene (9.5 g, 53.6mmol, 1.1 equiv.) was added and the reaction was stirred at roomtemperature for 24 hours. The reaction mixture was diluted with ice-coldwater (150 mL) and extracted with ethyl acetate (2×1 L). The aqueouslayer was acidified to pH 3.0, with 3M HCl (16 mL) and extracted withethyl acetate (1 L). The organic layer was washed with saturated brinesolution (1 L) and water (3×1 L), dried over sodium sulfate (150 g) andconcentrated under reduced pressure. The crude material was absorbed onto celite (30 g) and purified on an Interchim automated chromatographysystem (Sorbtech silica gel column, 330 g), eluting with a gradient of 0to 100% ethyl acetate in heptanes to give compound 42-2d (2.34 g, 15%yield) as a viscous pale yellow oil.

Methyl N-(tert-butoxycarbonyl)-O-(thiophen-3-ylmethyl)-L-homoserinate(42-3d): Potassium carbonate (2.05 g, 14.8 mmol, 2.0 equiv.) was addedto solution of compound 42-2d (2.34 g, 7.4 mmol, 1.0 equiv.) in DMF (12mL). After stirring at room temperature for 10 minutes, methyl iodide(0.923 mL, 14.8 mmol, 2.0 equiv.) was added and the reaction was stirredat room temperature for 24 hours. The reaction mixture was diluted withethyl acetate (250 mL) and washed with saturated brine solution (3×250mL) and water (250 mL). The organic layer was dried over sodium sulfate(100 g) and concentrated under reduced pressure. The crude material wasabsorbed on to celite (5 g) and purified on an Interchim automatedchromatography system (Sorbtech silica gel column, 80 g), eluting with agradient of 0 to 50% ethyl acetate in heptanes to give compound 42-3d(1.9 g, 77% yield) as a light yellow oil.

tert-Butyl(S)-(1-chloro-2-oxo-5-(thiophen-3-ylmethoxy)pentan-3-yl)carbamate(42-4d): 1.6 M n-BuLi in hexanes (9.5 mL, 15.2 mmol, 5.0 equiv.) wasadded to diisopropylamine (2.34 mL, 16.7 mmol, 5.5 equiv.) in THF (15mL) at −78° C. The reaction was warmed to 0° C. for 5 minutes, cooled to−78° C. and slowly added over 30 minutes to compound 42-3d (1.0 g, 3.0mmol, 1.0 equiv.) in THF (15 mL) at −78° C. After stirring at −78° C.for 25 minutes, acetic acid (6 mL) was added drop wise at −78° C. Thereaction was diluted with saturated brine solution (500 mL) andextracted with ethyl acetate (500 mL). The organic layer was washed withsaturated bicarbonate solution (3×500 mL) and water (250 mL). The ethylacetate layer was dried over sodium sulfate (100 g) and concentratedunder reduced pressure. The crude material was absorbed on to celite (4g) and purified on an Interchim automated chromatography system(Sorbtech silica gel column, 80 g), eluting with a gradient of 0 to 80%ethyl acetate in heptanes to give compound 42-4d (0.938 g, 82% yield) asa light yellow oil.

tert-Butyl(S)-(2-oxo-1-(2,3,5,6-tetrafluorophenoxy)-5-(thiophen-3-ylmethoxy)pentan-3-yl)carbamate(42-5d): Sodium iodide (0.56 g, 3.7 mmol, 1.5 equiv.) and potassium saltof 2,3,5,6-tetrafluorophenol (0.763 g, 3.7 mmol, 1.5 equiv.) was addedto a solution of compound 42-4d (0.938 g, 2.5 mmol, 1.0 equiv.) inacetone (10 mL). After stirring at room temperature for 18 hours, thesolvents were removed under reduced pressure. The residue was dilutedwith ethyl acetate (500 mL) and washed with saturated brine (250 mL).The organic layer was dried over sodium sulfate (50 g), filtered andconcentrated under reduced pressure. The crude material was absorbed onto celite (4 g) and purified on an Interchim automated chromatographysystem (Sorbtech silica gel column, 80 g), eluting with a gradient of 0to 40% ethyl acetate in heptanes to give compound 42-5d (0.754 g, 63%yield) as a light yellow oil.

(S)-3-Amino-1-(2,3,5,6-tetrafluorophenoxy)-5-(thiophen-3-ylmethoxy)pentan-2-onehydrogen chloride (42-6d): 4M HCl in 1,4-dioxane (0.78 mL, 3.1 mmol, 2.0equiv.) was added dropwise to a solution of compound 42-5d (0.75 g, 1.6mmol, 1 equiv.) in acetonitrile (10 mL) at 5° C. The mixture was thenwarmed to room temperature and stirred for 24 hours. The mixture wasconcentrated under reduced pressure. The solid was triturated withheptanes (3×10 mL), decanted and dried under vacuum to give compound42-6d (0.514 g, 79% yield) as an off-white solid.

Example 4

N¹—(2,6-difluorophenyl)-N²—((S)-1-oxo-1-(((S)-2-oxo-1-(2,3,5,6-tetrafluorophenoxy)-5-(thiophen-3-ylmethoxy)pentan-3-yl)amino)propan-2-yl)oxalamide(42-D, Example 4): EDC.HCl (0.146 g, 0.8 mmol, 1.1 equiv.) was added toa suspension of compound 8 (0.189 g, 0.7 mmol, 1.0 equiv.) and HOAt(0.113 g, 1.0 mmol, 1.2 equiv.) in acetonitrile (8 mL). The mixture wasstirred at room temperature until all solids dissolved. Compound 42-6d(0.288 g, 0.7 mmol, 1.0 equiv.) and triethylamine (0.193 mL, 1.4 mmol,2.0 equiv.) were sequentially added and the mixture was stirred at roomtemperature for 20 hours. The mixture was diluted with ethyl acetate(250 mL) and washed with saturated sodium bicarbonate (250 mL) andsaturated brine (250 mL). The organic layer was dried over sodiumsulfate (100 g), filtered and concentrated under reduced pressure. Thecrude material was absorbed on to celite (3 g) and purified on anInterchim automated chromatography system (Sorbtech silica gel column,25 g), eluting with a gradient of 0 to 90% ethyl acetate in heptanes togive 42-D, (Example 4) (0.2 g, 45% yield) as a white solid, (Mass Spec.m/z=632.1 (M+H).

Example 5

tert-Butyl (S)-(1-bromo-5-methoxy-2-oxopentan-3-yl)carbamate (57-3):Isobutyl chloroformate (0.84 mL, 6.43 mmol, 1.5 equiv.) was addeddropwise to a solution of N-(tert-butoxycarbonyl)-O-methyl-L-homoserine(57-1) (1.0 g, 4.29 mmol, 1 equiv.) and N-methylmorpholine (0.75 mL,6.86 mmol, 1.6 equiv.) in THF (18 mL) at −10° C. After stirring at −10°C. for 20 minutes, the reaction was filtered through celite andconcentrated under reduced pressure to give the mixed anhydride as acolorless oil, which was used subsequently.

Diazomethane preparation: A solution ofN-methyl-N′-nitroso-p-toluenesulfonamide (Diazald®, 2.76 g, 12.87 mmol,1 equiv.) in diethyl ether (10 mL) was added through an addition funnelto a mixture of potassium hydroxide (2.54 g, 38.6 mmol, 3 equiv.) inethanol (6 mL) and water (5 mL) in an oil bath at 65° C. The receivingflask to collect the ethereal solution of diazomethane was cooled in anice-bath and the Diazald® solution was added at such a rate as thatallowed for a dropwise distillation into the receiving flask. When allof the Diazald® solution had been added, additional diethyl ether (3 mL)was added through the addition funnel until the distillate was clear (noremaining diazomethane). After cooling to room temperature, the mixturein the distillation flask was quenched slowly with acetic acid until theyellow color disappeared.

A solution of freshly prepared mixed anhydride above (1.37 g, 4.29 mmol,1 equiv.) in diethyl ether (25 mL) was placed in a clear-seal jointflask and cooled to 0° C. in an ice bath. The freshly prepareddiazomethane ethereal solution (˜12.87 mmol, 3 equiv.) was added throughan addition funnel dropwise while keeping it cold. The resulting mixturewas stirred at 0° C. for 15 minutes, warmed to room temperature andstirred for 30 minutes. The reaction was cooled to 0° C. Meanwhile amixture of 48% aqueous HBr (4.0 mL, 30.0 mmol, 7 equiv.) and acetic acid(4.0 mL) was cooled to 0° C. and added to the above reaction mixtureslowly at 0° C. The mixture was stirred at 0° C. for 15 minutes, warmedto room temperature and stirred for 30 minutes. The mixture was dilutedwith diethyl ether (10 mL), washed with water (3×15 mL), dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified on an InterChim automated chromatography system(120 g SorbTech silica gel column), eluting with a gradient of 0 to 40%ethyl acetate in heptanes to give compound 57-3 (0.67 g, 50% yield) as acolorless oil.

tert-Butyl(S)-(5-methoxy-2-oxo-1-(2,3,5,6-tetrafluorophenoxy)pentan-3-yl)carbamate(57-4): Potassium fluoride (502 mg, 8.64 mmol, 4 equiv.) was added to asolution of compound 57-3 (0.67 g, 2.16 mmol, 1 equiv.) and2,3,5,6-tetrafluorophenol (395 mg, 2.38 mmol, 1.1 equiv.) in DMF (10mL). After stirring at room temperature for 16 hours, the reaction wasdiluted with ethyl acetate (15 mL), washed with saturated sodiumbicarbonate (20 mL) and saturated brine (20 mL). The organic layer wasdried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified on an InterChim automatedchromatography system (120 g SorbTech silica gel column), eluting with agradient of 0 to 40% ethyl acetate in heptanes to give compound 57-4(0.53 g, 62% yield) as a colorless oil.

(S)-3-Amino-5-methoxy-1-(2,3,5,6-tetrafluorophenoxy)pentan-2-onehydrochloride (57-5): 4M HCl in 1,4-dioxane (0.34 mL, 1.34 mmol, 1.0equiv.) was added dropwise to a solution of compound 57-4 (0.53 g, 1.34mmol, 1 equiv.) in acetonitrile (10 mL) at 5° C. The mixture was warmedto room temperature and stirred overnight. LCMS indicated that thereaction was not complete. Additional 4M HCl in 1,4-dioxane (0.34 mL,1.34 mmol, 1.0 equiv.) was added and the mixture was stirred for 6 hoursat which time LCMS indicated that the reaction was complete. The mixturewas concentrated under reduced pressure to give compound 57-5 (0.48 g,100% yield) as a light yellow liquid.

N¹—(2,6-Difluorophenyl)-N²—((S)-1-(((S)-5-methoxy-2-oxo-1-(2,3,5,6-tetrafluorophenoxy)pentan-3-yl)amino)-1-oxopropan-2-yl)oxalamide(Compound 57-A, Example 5): EDC.HCl (0.305 g, 1.59 mmol, 1.1 equiv.) wasadded to a suspension of compound 8 (0.393 g, 1.446 mmol, 1.0 equiv.)and HOAt (0.237 g, 1.74 mmol, 1.2 equiv.) in acetonitrile (10 mL). Themixture was stirred at room temperature until all solids dissolved.Compound 57-5 (0.48 g, 1.446 mmol, 1.0 equiv.) and triethylamine (0.40mL, 2.89 mmol, 2.0 equiv.) were sequentially added and the mixture wasstirred at room temperature overnight. LC-MS analysis indicated that thereaction was complete. The mixture was diluted with ethyl acetate (20mL) and washed with saturated sodium bicarbonate (20 mL) and saturatedbrine (20 mL). The organic layer was dried over sodium sulfate, filteredand concentrated under reduced pressure. The crude product was purifiedon an Interchim automated chromatography system (120 g column), elutingwith a gradient of 0 to 60% ethyl acetate in heptanes to give 57-A,(Example 5) (0.51 g, 64% yield) as a white solid, (Mass Spec. m/z=550.1(M+H).

Example 6

Benzyl (S)-6-bromo-4-((tert-butoxycarbonyl)amino)-5-oxohexanoate (58-3):Isobutyl chloroformate (5.84 mL, 45.0 mmol, 1.5 equiv.) was addeddropwise to a solution of(S)-5-(benzyloxy)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoic acid(58-1) (10.12 g, 30.0 mmol, 1 equiv.) and N-methylmorpholine (5.28 mL,48 mmol, 1.6 equiv.) in THF (100 mL) at −10° C. After stirring at −10°C. for 20 minutes, the reaction was filtered through celite andconcentrated under reduced pressure to give the mixed anhydride as acolorless oil, which was used subsequently.

Diazomethane preparation: A solution ofN-methyl-N′-nitroso-p-toluenesulfonamide (Diazald®, 19.28 g, 90.0 mmol,1 equiv.) in diethyl ether (66 mL) was added through an addition funnelto a mixture of potassium hydroxide (15.12 g, 270 mmol, 3 equiv.) inethanol (30 mL) and water (26 mL) in an oil bath at 65° C. The receivingflask to collect the ethereal solution of diazomethane was cooled in anice-bath and the Diazald® solution was added at such a rate as thatallowed for a dropwise distillation into the receiving flask. When allof the Diazald® solution had been added, additional diethyl ether (10mL) was added through the addition funnel until the distillate was clear(no remaining diazomethane). After cooling to room temperature, themixture in the distillation flask was quenched slowly with acetic aciduntil the yellow color disappeared.

A solution of freshly prepared mixed anhydride above (12.70 g, 30.0mmol, 1 equiv.) in diethyl ether (110 mL) was placed in a clear-sealjoint flask and cooled to 0° C. in an ice bath. The freshly prepareddiazomethane ethereal solution (˜90.0 mmol, 3 equiv.) was added throughan addition funnel dropwise while keeping it cold. The resulting mixturewas stirred at 0° C. for 15 minutes, warmed to room temperature andstirred for 30 minutes. The reaction was cooled to 0° C. Meanwhile amixture of 48% aqueous HBr (24 mL, 210.0 mmol, 7 equiv.) and acetic acid(24.0 mL) was cooled to 0° C. and added to the above reaction mixtureslowly at 0° C. The mixture was stirred at 0° C. for 15 minutes, warmedto room temperature and stirred for 30 minutes. The mixture was dilutedwith diethyl ether (80 mL), washed with water (3×100 mL), dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified on an InterChim automated chromatography system(220 g SorbTech silica gel column), eluting with a gradient of 0 to 40%ethyl acetate in heptanes to give compound 58-3 (8.6 g, 69% yield) as acolorless oil.

Benzyl(S)-4-((tert-butoxycarbonyl)amino)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoate(58-4): Potassium fluoride (4.83 g, 83.08 mmol, 4 equiv.) was added to asolution of compound 58-3 (8.6 g, 20.77 mmol, 1 equiv.) and2,3,5,6-tetrafluorophenol (3.79 g, 22.85 mmol, 1.1 equiv.) in DMF (100mL). After stirring at room temperature for 16 hours, the reaction wasdiluted with ethyl acetate (150 mL), washed with saturated sodiumbicarbonate (200 mL) and saturated brine (200 mL). The organic layer wasdried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified on an InterChim automatedchromatography system (220 g SorbTech silica gel column), eluting with agradient of 0 to 40% ethyl acetate in heptanes to give compound 58-4(6.13 g, 59% yield) as a colorless oil.

(S)-3-Amino-5-methoxy-1-(2,3,5,6-tetrafluorophenoxy)pentan-2-onehydrochloride (58-5): 4M HCl in 1,4-dioxane (3.1 mL, 12.3 mmol, 1.0equiv.) was added dropwise to a solution of compound 58-4 (6.13 g, 12.28mmol, 1 equiv.) in acetonitrile (80 mL) at 5° C. The mixture was warmedto room temperature and stirred overnight. LCMS indicated that thereaction was not complete. Additional 4M HCl in 1,4-dioxane (3.1 mL,12.3 mmol, 1.0 equiv.) was added and the mixture was stirred for 6 hoursat which time LCMS indicated that the reaction was complete. The mixturewas concentrated under reduced pressure to give compound 58-5 (6.2 g,100% yield) as a light yellow solid.

Benzyl (S)-4-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido)propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoate (58-6):EDC.HCl (0.483 g, 2.52 mmol, 1.1 equiv.) was added to a suspension ofcompound 8 (0.623 g, 2.29 mmol, 1.0 equiv.) and HOAt (0.374 g, 2.75mmol, 1.2 equiv.) in acetonitrile (15 mL). The mixture was stirred atroom temperature until all solids dissolved. Compound 58-5 (1.0 g, 2.29mmol, 1.0 equiv.) and triethylamine (0.638 mL, 4.58 mmol, 2.0 equiv.)were sequentially added and the mixture was stirred at room temperatureovernight. LC-MS analysis indicated that the reaction was complete. Themixture was diluted with ethyl acetate (30 mL) and washed with saturatedsodium bicarbonate (30 mL) and saturated brine (30 mL). The organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure. The crude product was purified on an Interchimautomated chromatography system (80 g column), eluting with a gradientof 0 to 60% ethyl acetate in heptanes to give compound 58-6 (0.72 g, 48%yield) as a white solid.

(S)-4-((S)-2-(2-((2,6-Difluorophenyl)amino)-2-oxoacetamido)propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoicacid (Compound 58-A, Example 6): A suspension of compound 58-6 (0.72 g,1.10 mmol, 1 equiv.) and 10% palladium on carbon (0.072 g, 50% wet) in amixture of THF (11 mL) and ethyl acetate (3.5 mL) was hydrogenated @25psi for 2 hours. The reaction mixture was filtered through celite andconcentrated under reduced pressure. The residue was purified on anInterchim automated chromatography system (120 g column), eluting with agradient of 0 to 10% methanol in dichloromethane to give compound 58-A,(Example 6) (0.56 g, 90% yield) as a white solid, (Mass Spec. m/z=564.2(M+H).

Example 7

Methyl O-benzyl-N-(tert-butoxycarbonyl)-L-homoserinate (56-1): Potassiumcarbonate (5.53 g, 40.0 mmol, 2.0 equiv.) was added to a solution ofcompound 25-1 (6.18 g, 20.0 mmol, 1.0 equiv.) in DMF (25 mL). Afterstirring at room temperature for 15 minutes, methyl iodide (2.49 mL,40.0 mmol, 2.0 equiv.) was added and the reaction was stirred at roomtemperature for 16 hours. The reaction mixture was diluted with ethylacetate (100 mL) and washed with water (3×50 mL) and saturated brinesolution (50 mL). The organic layer was dried over sodium sulfate,filtered and concentrated under reduced pressure. The crude material waspurified on an Interchim automated chromatography system (Sorbtechsilica gel column, 120 g), eluting with a gradient of 0 to 35% ethylacetate in heptanes to give compound 56-1 (5.6 g, 87% yield) as acolorless oil.

tert-Butyl (S)-(5-(benzyloxy)-1-chloro-2-oxopentan-3-yl)carbamate(56-2): Chloroiodomethane (1.16 mL, 16.0 mmol, 4.0 equiv.) intetrahydrofuran (10 mL) was added slowly to a solution compound 56-1(1.29 g, 4.0 mmol, 1.0 equiv.) in tetrahydrofuran (20 mL) at −78° C.Fresh prepared lithium diisopropylamide solution was slowly added over30 minutes while maintaining the temperature below −70° C. Afterstirring at −78° C. for 45 minutes, acetic acid (1.7 mL) intetrahydrofuran (10 mL) was slowly added while maintaining thetemperature at −65° C. After stirring at −78° C. for 10 minutes, thereaction was diluted with saturated brine (60 mL) and extracted withethyl acetate (60 mL). The organic layer was washed with saturatedbicarbonate (3×50 mL) and water (50 mL). The ethyl acetate layer wasdried over sodium sulfate, filtered and concentrated under reducedpressure. The crude material was purified on an Interchim automatedchromatography system (Sorbtech silica gel column, 120 g), eluting witha gradient of 0 to 20% ethyl acetate in heptanes to give compound 56-2(0.92 g, 67% yield) as a light yellow oil.

Lithium diisopropylamide solution preparation: 1.6 M n-BuLi in hexane(12.25 mL, 20.0 mmol, 5.0 equiv.) was added to diisopropylamine (3.08mL, 22.0 mmol, 5.5 equiv.) in THF (20 mL) at −78° C. The reaction waswarmed to 0° C. for 30 minutes, cooled to −40° C.

tert-Butyl(S)-(5-(benzyloxy)-2-oxo-1-(2,3,5,6-tetrafluorophenoxy)pentan-3-yl)carbamate(25-4): Sodium iodide (605 mg, 4.03 mmol, 1.5 equiv.) and potassium2,3,5,6-tetrafluorophenolate (823 mg, 4.03 mmol, 1.5 equiv.) were addedto a solution of compound 56-2 (0.92 g, 2.69 mmol, 1.0 equiv.) inacetone (15 mL). After stirring at room temperature for 20 hours, thesolvents were removed under reduced pressure. The residue was dilutedwith ethyl acetate (50 mL) and washed with saturated brine (50 mL). Theorganic layer was dried over sodium sulfate, filtered and concentratedunder reduced pressure. The crude material was purified on an Interchimautomated chromatography system (Sorbtech silica gel column, 80 g),eluting with a gradient of 0 to 40% ethyl acetate in heptanes to givecompound 25-4 (1.10 g, 87% yield) as a light yellow oil.

(S)-3-Amino-5-(benzyloxy)-1-(2,3,5,6-tetrafluorophenoxy)pentan-2-onehydrochloride (25-5): 4M HCl in 1,4-dioxane (0.80 mL, 3.20 mmol, 1.2equiv.) was added dropwise to a solution of compound 25-4 (1.25 g, 2.65mmol, 1.0 equiv.) in acetonitrile (15 mL) at 5° C. The mixture was thenwarmed to room temperature and stirred overnight. LCMS indicated thatthe reaction was not complete. Additional 4M HCl in 1,4-dioxane (0.53mL, 2.12 mmol, 0.8 equiv.) was added and the mixture was stirred for 6hours at which time LCMS indicated that the reaction was complete. Themixture was concentrated under reduced pressure to give compound 25-5(1.15 g, 98% yield) as a light yellow solid.

N¹—((S)-1-(((S)-5-(Benzyloxy)-2-oxo-1-(2,3,5,6-tetrafluorophenoxy)pentan-3-yl)amino)-1-oxopropan-2-yl)-N²—(2,6-difluorophenyl)oxalamide(19-6): EDC.HCl (0.559 g, 2.92 mmol, 1.1 equiv.) was added to asuspension of compound 8 (0.721 g, 2.65 mmol, 1.0 equiv.) and HOAt(0.433 g, 3.18 mmol, 1.2 equiv.) in acetonitrile (15 mL). The mixturewas stirred at room temperature until all solids dissolved. Compound25-5 (1.08 g, 2.65 mmol, 1.0 equiv.) and triethylamine (0.74 mL, 5.3mmol, 2.0 equiv.) were sequentially added and the mixture was stirred atroom temperature overnight. LC-MS analysis indicated that the reactionwas complete. The mixture was diluted with ethyl acetate (40 mL) andwashed with saturated sodium bicarbonate (30 mL) and saturated brine (30mL). The organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was purified onan Interchim automated system (120 g column), eluting with a gradient of0 to 60% ethyl acetate in heptanes to give compound 19-6 (1.02 g, 62%yield) as a light yellow solid.

N¹—(2,6-Difluorophenyl)-N²—((S)-1-(((S)-5-hydroxy-2-oxo-1-(2,3,5,6-tetrafluorophenoxy)pentan-3-yl)amino)-1-oxopropan-2-yl)oxalamide(19-7): A mixture of 19-6 (1.02 g, 1.63 mmol, 1.0 equiv.) and 10%palladium on activated carbon (102 mg, 50% wet) in tetrahydrofuran (10mL) and methanol (10 mL) was hydrogenated @ 45 psi for 3 hours. LC-MSanalysis indicated that the reaction was complete. The mixture wasfiltered through Celite (15 g), which was washed with additionalmethanol (25 mL). The crude product was purified on an Interchimautomated system (120 g column), eluting with a gradient of 0 to 80%ethyl acetate in heptanes to give compound 19-7 (350 mg, 40% yield) as awhite solid.

(S)-3-((S)-2-(2-((2,6-Difluorophenyl)amino)-2-oxoacetamido)propanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentylphenyl carbonate (56-A, Example 7): Phenyl chloroformate (0.13 mL, 1.05mmol, 1.0 equiv.) was added at 0° C. to a solution of compound 19-7 (565mg, 1.05 mmol, 1.0 equiv.), pyridine (0.84 mL, 10.5 mmol, 10.0 equiv.)and 4-dimethylaminopyridine (81 mg, 0.66 mmol, 0.63 equiv.) in 12 mL ofdichloromethane. The reaction mixture was stirred at room temperaturefor 2 hours. Additional phenyl chloroformate (0.20 mL, 1.58 mmol, 1.5equiv.) was added into the reaction. The mixture was stirred at roomtemperature for 2 hours, at which point LC-MS analysis indicated thatthe reaction was complete. The reaction mixture was washed with water(2×10 mL). The combined aqueous layers were extracted withdichloromethane (2×10 mL). The combined organic layers were washed withsaturated ammonium chloride (2×10 mL) and saturated brine (10 mL). Theorganic layer was dried over sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified on InterChim automatedchromatography system (120 g, SorbTech silica gel column), eluting witha gradient of 0 to 25% ethyl acetate in dichloromethane. The product wastriturated with diethyl ether (10 mL) to give the compound 56-A,(Example 7) (160 mg, 17% yield) as a yellow solid, (Mass Spec. m/z=656.2(M+H).

Example 8

(S)-3-((S)-2-(2-((2,6-Difluorophenyl)amino)-2-oxoacetamido)propanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentylbenzoate (56-B, Example 8): Benzoyl chloride (0.34 mL, 2.97 mmol, 2.5equiv.) was added at 0° C. to a solution of compound 19-7 (635 mg, 1.19mmol, 1.0 equiv.), pyridine (0.95 mL, 11.9 mmol, 10.0 equiv.) and4-dimethylaminopyridine (91 mg, 0.75 mmol, 0.63 equiv.) in 12 mL ofdichloromethane. After stirring at room temperature for 2 hours, thereaction mixture was washed with water (2×10 mL). The combined aqueouslayers were extracted with dichloromethane (2×10 mL). The combinedorganic layers were washed with saturated ammonium chloride (2×10 mL)and saturated brine (10 mL). The organic layer was dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified on InterChim automated chromatography system (120 g,SorbTech silica gel column), eluting with a gradient of 0 to 25% ethylacetate in dichloromethane. The product was triturated with diethylether (10 mL) to give the compound 56-B, (Example 8) (280 mg, 37% yield)as a yellow solid, (Mass Spec. m/z=640.2 (M+H).

Example 9

Ethyl 2-((2,6-difluorophenyl)amino)-2-oxoacetate (3): Triethylamine(27.2 mL, 193.8 mmol, 1 equiv.) was added to a solution of2,6-difluoroaniline (25.0 g, 193.8 mmol, 1 equiv.) in THF (1 L) at 0-5°C. Ethyl oxalyl chloride (21.6 mL, 193.8 mmol, 1 equiv.) was addeddropwise over 60 minutes, while maintain the temperature <5° C. Thereaction was warmed to room temperature and stirred for 24 hours. Thereaction was filtered through celite, the celite was washed with methylt-butyl ether (500 mL) and the combined organic layers were washed witha 1N HCl (2×200 mL) and water (400 mL). The organic layer was dried oversodium sulfate, filtered and concentrated under reduced pressure to givethe desired product as a beige oil (44.8 g, quantitative yield).

2-((2,6-Difluorophenyl)amino)-2-oxoacetic acid (4): 1N Lithium hydroxide(233 mL, 233 mmol, 1.2 equiv.) was added to a solution of compound 3(44.8 g, 193.8 mmol, 1 equiv.) in THF (233 mL). After stirring at roomtemperature for 4 hours, the reaction was cooled to 0° C. and acidifiedwith concentrated HCl to pH 2. The aqueous mix was saturated with sodiumchloride and extracted with ethyl acetate (6×200 mL). The combinedorganic layers were dried over sodium sulfate, filtered and concentratedunder reduced pressure to give the desired product as a white solid(18.3 g, 47% yield).

Benzyl (2-((2,6-difluorophenyl)amino)-2-oxoacetyl)glycinate (60-1):N′-ethylcarbodiimide hydrochloride (3.99 g, 20.83 mmol, 1.4 equiv.) wasadded to a suspension of compound 4 (2.99 g, 14.88 mmol, 1.0 equiv.),1-hydroxy-7-azabenzotriazole (2.85 g, 20.83 mmol, 1.4 equiv.) inacetonitrile (200 mL). The mixture was stirred at room temperature untilall solids dissolved. Benzyl glycinate hydrochloride (3.0 g, 14.88 mmol,1.0 equiv.) and N-methylmorpholine (3.01 g, 29.76 mmol, 2.0 equiv.) wereadded and the mixture was stirred at room temperature overnight. LC-MSanalysis indicated that the reaction was complete. The mixture wasconcentrated under reduced pressure and the wet solid was diluted inethyl acetate (60 mL) and water (20 mL). The layers were separated, andthe aqueous layer was extracted with ethyl acetate (2×15 mL). Thecombined organic layers were washed with saturated brine (100 mL), driedover sodium sulfate, filtered and concentrated under reduced pressure.The residue was purified on an InterChim automated chromatography system(220 g SorbTech silica gel column), eluting with a gradient of 0 to 5%ethyl acetate in dichloromethane. The product was further purified on anInterChim automated chromatography system (220 g SorbTech silica gelcolumn), eluting with a gradient of 0 to 50% ethyl acetate in heptanesto give compound 60-1 (1.90 g, 37% yield) as a white solid.

(2-((2,6-difluorophenyl)amino)-2-oxoacetyl)glycine (60-2): A mixture ofcompound 60-1 (1.86 g, 5.34 mmol, 1.0 equiv.) and 10% palladium onactivated carbon (186 mg, 50% wet) in tetrahydrofuran (11.5 mL) andethyl acetate (3.5 mL) was hydrogenated @ 25 psi for 2 hours. LC-MSanalysis indicated that the reaction was complete. The mixture wasfiltered through Celite (15 g) to give compound 60-1 (1.31 mg, 95%yield) as a white solid.

Benzyl(S)-4-(2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido)acetamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoate(60-3): N′-ethylcarbodiimide hydrochloride (0.388 g, 2.02 mmol, 1.1equiv.) was added to a suspension of compound 60-2 (0.474 g, 1.84 mmol,1.0 equiv.) and 1-hydroxy-7-azabenzotriazole (0.301 g, 2.21 mmol, 1.2equiv.) in acetonitrile (15 mL). The mixture was stirred at roomtemperature until all solids dissolved. Compound 58-5 (0.80 g, 1.84mmol, 1.0 equiv.) and triethylamine (0.51 mL, 3.68 mmol, 2.0 equiv.)were sequentially added and the mixture was stirred at room temperatureovernight. LC-MS analysis indicated that the reaction was complete. Themixture was diluted with ethyl acetate (40 mL) and washed with saturatedsodium bicarbonate (30 mL) and saturated brine (30 mL). The organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure. The crude product was purified on an Interchimautomated chromatography system (120 g column), eluting with a gradientof 0 to 70% ethyl acetate in heptanes to give compound 60-3 (0.42 g, 36%yield) as a white solid.

(S)-4-(2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido)acetamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoicacid (60-A, Example 9): A mixture of compound 60-3 (0.42 g, 0.657 mmol,1.0 equiv.) and 10% palladium on activated carbon (42 mg, 50% wet) intetrahydrofuran (15 mL) and ethyl acetate (5 mL) was hydrogenated @ 25psi for 2 hours. LC-MS analysis indicated that the reaction wascomplete. The mixture was filtered through Celite (15 g), which waswashed with additional methanol (25 mL). The crude product was purifiedon an Interchim automated chromatography system (80 g column), elutingwith a gradient of 0 to 10% methanol in dichloromethane. The product wastriturated with diethyl ether (10 mL) to give the compound 60-A,(Example 9), (210 mg, 58% yield) as a white solid, (Mass Spec. m/z=550.1(M+H).

Example 10

Benzyl (S)-6-bromo-4-((tert-butoxycarbonyl)amino)-5-oxohexanoate (58-3):Isobutyl chloroformate (5.84 mL, 45.0 mmol, 1.5 equiv.) was addeddropwise to a solution of(S)-5-(benzyloxy)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoic acid(58-1) (10.12 g, 30.0 mmol, 1 equiv.) and N-methylmorpholine (5.28 mL,48 mmol, 1.6 equiv.) in THF (100 mL) at −10° C. After stirring at −10°C. for 20 minutes, the reaction was filtered through celite andconcentrated under reduced pressure to give the mixed anhydride (12.7 g)as a colorless oil, which was used subsequently.

Diazomethane preparation: A solution ofN-methyl-N′-nitroso-p-toluenesulfonamide (Diazald®, 19.28 g, 90.0 mmol,1 equiv.) in diethyl ether (66 mL) was added through an addition funnelto a mixture of potassium hydroxide (15.12 g, 270 mmol, 3 equiv.) inethanol (30 mL) and water (26 mL) in an oil bath at 65° C. The receivingflask to collect the ethereal solution of diazomethane was cooled in anice-bath and the Diazald® solution was added at such a rate as thatallowed for a dropwise distillation into the receiving flask. When allof the Diazald® solution had been added, additional diethyl ether (10mL) was added through the addition funnel until the distillate was clear(no remaining diazomethane). After cooling to room temperature, themixture in the distillation flask was quenched slowly with acetic aciduntil the yellow color disappeared.

A solution of freshly prepared mixed anhydride above (12.7 g, 30.0 mmol,1 equiv.) in diethyl ether (110 mL) was placed in a clear-seal jointflask and cooled to 0° C. in an ice bath. The freshly prepareddiazomethane ethereal solution (˜90.0 mmol, 3 equiv.) was added throughan addition funnel dropwise while keeping it cold. The resulting mixturewas stirred at 0° C. for 15 minutes, warmed to room temperature andstirred for 30 minutes. The reaction was cooled to 0° C. Meanwhile amixture of 48% aqueous HBr (24 mL, 210.0 mmol, 7 equiv.) and acetic acid(24.0 mL) was cooled to 0° C. and added to the above reaction mixtureslowly at 0° C. The mixture was stirred at 0° C. for 15 minutes, warmedto room temperature and stirred for 30 minutes. The mixture was dilutedwith diethyl ether (120 mL), washed with water (3×120 mL), dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified on an InterChim automated chromatography system(220 g SorbTech silica gel column), eluting with a gradient of 0 to 30%ethyl acetate in heptanes to give compound 58-3 (7.26 g, 59% yield) as awhite solid.

Benzyl(S)-6-(3,5-bis(trifluoromethyl)phenoxy)-4-((tert-butoxycarbonyl)amino)-5-oxohexanoate(59-1): Potassium fluoride (3.93 g, 67.6 mmol, 4 equiv.) was added to asolution of compound 58-3 (7.0 g, 16.9 mmol, 1 equiv.) and3,5-bis(trifluoromethyl)phenol (2.8 mL, 18.6 mmol, 1.1 equiv.) in DMF(70 mL). After stirring at room temperature for 18 hours, the reactionwas diluted with ethyl acetate (120 mL), washed with saturated sodiumbicarbonate (180 mL) and saturated brine (180 mL). The organic layer wasdried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified on an InterChim automatedchromatography system (220 g RediSepRf silica gel column), eluting witha gradient of 0 to 25% ethyl acetate in heptanes to give compound 59-1(6.0 g, 63% yield) as a white solid.

Benzyl (S)-4-amino-6-(3,5-bis(trifluoromethyl)phenoxy)-5-oxohexanoatehydrochloride (59-2): 4M HCl in 1,4-dioxane (2.9 mL, 11.7 mmol, 1.2equiv.) was added dropwise to a solution of compound 59-1 (5.5 g, 9.76mmol, 1 equiv.) in acetonitrile (100 mL) at 0 to 5° C. The mixture waswarmed to room temperature and stirred for 6.5 hours. LCMS indicatedthat the reaction was not complete. Additional 4M HCl in 1,4-dioxane(2.0 mL, 7.8 mmol, 0.8 equiv.) was added and the mixture was stirred for16 hours at which time LCMS indicated that the reaction was complete.The mixture was concentrated under reduced pressure to give compound59-2 (4.6 g, 95% yield) as a white solid, which was used subsequently.

Benzyl(S)-6-(3,5-bis(trifluoromethyl)phenoxy)-4-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido)propanamido)-5-oxohexanoate(59-3):(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.84 g, 2.2 mmol, 1.1 equiv.) was added to asolution of compound 8 (0.55 g, 2.0 mmol, 1 equiv.) in dimethylformamide(10 mL) at room temperature. After stirring at room temperature for 10minutes, compound 59-2 (1.0 g, 2.0 mmol, 1 equiv.) andN,N-diisopropylethylamine (1.1 mL, 6.0 mmol, 3 equiv.) were sequentiallyadded. After stirring at room temperature for 18 hours, the reactionmixture was diluted with ethyl acetate (50 mL). The organic layer waswashed with water (2×30 mL), dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude material was purified onan Interchim automated chromatography system (80 g RediSepRf silica gelcolumn), eluting with a gradient of 0 to 60% ethyl acetate in heptanes.After concentrating the fractions under reduced pressure, the resultingsolid was dried under vacuum at 45° C. for 18 hours to give compound59-3 (0.72 g, 50% yield) as a yellowish solid.

(S)-6-(3,5-bis(trifluoromethyl)phenoxy)-4-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido)propanamido)-5-oxohexanoicacid (59-A, Example 10): A suspension of compound 59-3 (0.53 g, 0.74mmol, 1.0 equiv.) and 10% palladium on activated carbon (53 mg, 50% wet)in tetrahydrofuran (20 mL) was hydrogenated @ 25 psi for 2 hours. LC-MSanalysis indicated that the reaction was complete. The mixture wasfiltered through Celite (15 g), which was washed with tetrahydrofuran(3×50 mL). The filtrates were concentrated under reduced pressure andthe crude product was dissolved in dichloromethane (12 mL), adsorbedonto silica gel (15 g). The material was dry-loaded and purified on anInterchim automated system (40 g Sorbtech silica gel column), elutingwith a gradient of 0 to 8% methanol in dichloromethane. Afterconcentrating the fractions under reduced pressure, the resulting solidwas dried under vacuum at room temperature for 18 hours to give compound59-A, (Example 10) (0.25 g, 54% yield) as an off-white solid, (MassSpec. m/z=628.1 (M+H).

Example 11

Benzyl (S)-4-((S)-2-(2-((2-(tert-butyl)phenyl)amino)-2-oxoacetamido)propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoate (65-1):1-Hydroxy-7-azabenzotriazole (0.21 g, 1.51 mmol, 1.2 equiv.) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.29 g,1.51 mmol, 1.2 equiv.) were added sequentially to a solution of(2-((2-(tert-butyl)phenyl)amino)-2-oxoacetyl)-L-alanine, compound A,(0.37 g, 1.26 mmol, 1.0 equiv.) in acetonitrile (6 mL) and DMF (3 mL) atroom temperature. After stirring at room temperature for 1 hour,compound 58-5 (0.55 g, 1.26 mmol, 1.0 equiv.) and triethylamine (0.35mL, 2.52 mmol, 2 equiv.) were sequentially added. After stirring at roomtemperature for 2 days, the reaction was concentrated under reducedpressure. The residue was partitioned between ethyl acetate (10 mL) andwater (10 mL). Organic layer was washed with water (10 mL) andconcentrated under reduced pressure. The residue was purified on anInterchim automated chromatography system (SorbTech 24 g column),eluting with a gradient of 0 to 30% ethyl acetate in hexanes to give thedesired product (0.49 g, 58% yield) as a white solid.

(S)-4-((S)-2-(2-((2-(tert-Butyl)phenyl)amino)-2-oxoacetamido)propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoicacid (Compound 65-A, Example 11): A suspension of compound 65-1 (0.49 g,0.73 mmol, 1 equiv.) and 10% palladium on carbon (0.1 g, 50% wet) in THF(20 mL) and ethyl acetate (5 mL) was hydrogenated @ 20 psi for 2 hours.The reaction mixture was filtered through syringe filter andconcentrated under reduced pressure. The residue was purified twice onan Interchim automated chromatography system (RediSep Gold 12 g silicagel column), eluting each time with a gradient of 0 to 5% methanol indichloromethane to give compound 65-A, (Example 11) (140 mg, 33% yield)as a white solid, (Mass Spec. m/z=584.2 (M+H).

Example 12

2-((2,6-Difluorophenyl)amino)-2-oxoacetic acid (4) was prepared inscheme 1.

Ethyl2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido)-2-methylpropanoate(61-1): Compound 4 (1.5 g, 7.46 mmol, 1.0 equiv.) and1-hydroxy-7-azabenzotriazole (1.421 g, 10.44 mmol, 1.4 equiv.) weredissolved in acetonitrile (77.3 mL).1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.002 g,10.44 mmol, 1.4 equiv.) was added and the mixture was allowed to stir atroom temperature. After 10 minutes everything had dissolved.N-methylmorpholine (1.97 mL, 17.9 mmol, 2.4 equiv.) was added, followedby ethyl 2-amino-2-methylpropanoate-hydrochloride (1.25 g, 7.46 mmol,1.0 equiv.). After stirring at room temperature under nitrogenatmosphere for 20 hours, the reaction was warmed to 70° C. for 5additional hours, then cooled to room temperature. Ethyl acetate (100mL) and water (80 mL) were added and the layers separated. The aqueouslayer was extracted with ethyl acetate (3×75 mL). The combined organicslayers were washed with saturated brine (75 mL), dried with sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas dissolved in dichloromethane (10 mL), adsorbed onto Celite andpurified on an Interchim automated chromatography system (Sorbtechsilica gel column, 80 g), eluting with a gradient of 0 to 50% ethylacetate in dichloromethane to give compound 61-1 (0.749 g, 32% yield) asa white solid.

2-(2-((2,6-Difluorophenyl)amino)-2-oxoacetamido)-2-methylpropanoic acid(61-2): Lithium hydroxide (68.4 mg, 2.86 mmol, 1.2 equiv.) in water (2.8mL) was added to a solution of compound 61-1 (0.748 g, 2.37 mmol, 1.0equiv.) in tetrahydrofuran (9.3 mL). The mixture was allowed to stir atroom temperature for 3 days. Additional lithium hydroxide (34.2 mg, 1.43mmol) in water (0.7 mL) and added to the reaction mixture. After anotherday, additional lithium hydroxide (34.2 mg, 1.43 mmol) in water (0.4 mL)and added to the reaction mixture along with 1 mL tetrahydrofuran. After3 more hours, the reaction was cooled to 0° C. and adjusted to pH.=2with concentrated HCl (20 drops). The mixture was extracted with ethylacetate (3×10 mL). The combined organics layers were dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas diluted with a 3 to 1 mixture of toluene and ethyl acetate, stirredfor 30 minutes at 40° C. and concentrated under reduced pressure. Theresidue was dried under vacuum at 40° C. for 4 hours to give compound61-2 (0.629 g, 92% yield) as a white solid.

Benzyl(S)-4-(2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido)-2-methylpropanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoate(61-3): Compound 61-2 (0.200 g, 0.698 mmol, 1.0 equiv.) and1-hydroxybenzotriazole hydrate (0.132 g, 0.838 mmol, 1.2 equiv.) weredissolved in acetonitrile (3.9 mL).1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.161 g,0.838 mmol, 1.2 equiv.) was added and the mixture was allowed to stir atroom temperature under nitrogen atmosphere for 1 hour.Diisopropylethylamine (0.243 mL, 1.4 mmol, 2.0 equiv.) was added,followed by compound 58-5 (0.304 g, 0.698 mmol, 1.0 equiv.) inacetonitrile (0.4 mL). The reaction was allowed to stir at roomtemperature for 22 hours. Ethyl acetate (10 mL) and saturated sodiumbicarbonate (5 mL) were added and the layers were separated. The aqueouslayer was extracted with ethyl acetate (2×5 mL). The combined organiclayers were washed with saturated brine, dried with sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified on an Interchim automated chromatography system (Sorbtechsilica gel column, 12 g), eluting with a gradient of 5 to 50% ethylacetate in heptanes to give compound 61-3 (0.117 g, 25% yield) as alight yellow oil.

This procedure was repeated on 0.362 g scale of compound 61-2 to givecompound 61-3 (0.160 g, 19% yield) as a light yellow oil.

(S)-4-(2-(2-((2,6-Difluorophenyl)amino)-2-oxoacetamido)-2-methylpropanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoicacid (61-A, Example 12): A mixture of compound 61-3 (0.117 g, 0.175mmol, 1.0 equiv.) and 10% Pd/C (11.2 mg, 50% wet) in tetrahydrofuran (20mL) was hydrogenated @ 22 psi) for 2 hours. The reaction mixture wasfiltered through Celite, which was washed with tetrahydrofuran (25 mL).The filtrate was concentrated under reduced pressure and purified on aBűchi automated chromatography system (Sorbtech silica gel column, 12g), eluting with a gradient of 0 to 10% methanol in dichloromethane togive 63 mg of a pink solid. This solid was triturated in dichloromethane(2 mL) to give a white solid, which was dried under vacuum overnight at40° C. to give compound 61-A (43 mg, 42% yield) as a white powder.(RC-3-011)

This procedure was repeated on 0.180 g scale of compound 61-3 to givecompound 61-A (65.0 mg, 42% yield. The two batches were combined to give61-A, Example 12) (108 mg) as a white powder, (Mass Spec. m/z=578 (M+H).

Example 13

(S)-2-Amino-6-(benzyloxy)-6-oxohexanoic acid (63-1B): Benzyl alcohol(125 mL, 1.21 mole, 10 equiv.) was added dropwise to a suspension ofL-2-aminoadipic acid (63-1A) (19.5 g, 0.12 mole, 1 equiv.) in 12M HCl(10 mL, 0.12 mole, 1 equiv.). The mixture was heated at 100° C. for 1hour and then cooled to room temperature. Diethyl ether (700 mL) wasadded to the solution. The resulting solid was filtered, washed withdiethyl ether (3×100 mL) and dried under vacuum at room temperature for18 hours to give compound 63-1B (22.5 g, 65% yield) as a white solid.

(S)-6-(Benzyloxy)-2-((tert-butoxycarbonyl)amino)-6-oxohexanoic acid(63-1): Sodium hydroxide (2.5 g, 62.5 mmol, 1.2 equiv.) was added to asolution of compound 63-1B (15 g, 52.1 mmol, 1 equiv.) in the mixture ofacetonitrile (200 mL) and water (200 mL). The mixture was stirred atroom temperature for 15 minutes. Di-tert-butyldicarbonate (14.4 mL, 62.5mmol, 1.2 equiv.) was added to the reaction mixture and stirred for 18hours. LCMS analysis indicated reaction was not complete. Additionalsodium hydroxide (1.04 g, 26.1 mmol, 0.5 equiv.) anddi-tert-butyldicarbonate (6.0 mL, 26.1 mmol, 0.5 equiv.) were added andthe mixture was stirred for 6 hours at which time LCMS analysisindicated that the reaction was complete. The acetonitrile was removedunder reduced pressure. Saturated sodium bicarbonate (200 mL) was addedto the aqueous solution, which was extracted with diethyl ether (3×250mL) to remove unreacted di-tert-butyldicarbonate. The aqueous solutionwas cooled to 0° C. and adjusted to pH 1 with 5M hydrochloric acid (˜220mL). The mixture was extracted with ethyl acetate (3×500 mL). Thecombined organic layers were washed with saturated brine (3×500 mL),dried over sodium sulfate, filtered, and concentrated under reducedpressure. The resulting oil was dried under vacuum at room temperaturefor 18 hours to give compound 63-1 (15.7 g, 86% yield) as a yellowliquid.

Benzyl (S)-7-bromo-5-((tert-butoxycarbonyl)amino)-6-oxoheptanoate(63-3): Isobutyl chloroformate (5.84 mL, 45.0 mmol, 1.5 equiv.) wasadded dropwise to a solution of compound 63-1 (10.54 g, 30.0 mmol, 1equiv.) and N-methylmorpholine (5.28 mL, 48 mmol, 1.6 equiv.) in THF(100 mL) at −10° C. After stirring at −10° C. for 20 minutes, thereaction was filtered through celite and concentrated under reducedpressure to give the mixed anhydride (12.3 g) as a yellow oil, which wasused subsequently.

Diazomethane preparation: A solution ofN-methyl-N′-nitroso-p-toluenesulfonamide (Diazald®, 19.28 g, 90.0 mmol,1 equiv.) in diethyl ether (66 mL) was added through an addition funnelto a mixture of potassium hydroxide (15.12 g, 270 mmol, 3 equiv.) inethanol (30 mL) and water (26 mL) in an oil bath at 65° C. The receivingflask to collect the ethereal solution of diazomethane was cooled in anice-bath and the Diazald® solution was added at such a rate as thatallowed for a dropwise distillation into the receiving flask. When allof the Diazald® solution had been added, additional diethyl ether (10mL) was added through the addition funnel until the distillate was clear(no remaining diazomethane). After cooling to room temperature, themixture in the distillation flask was quenched slowly with acetic aciduntil the yellow color disappeared.

A solution of freshly prepared mixed anhydride above (12.7 g, 30.0 mmol,1 equiv.) in diethyl ether (110 mL) was placed in a clear-seal jointflask and cooled to 0° C. The freshly prepared diazomethane etherealsolution (˜90.0 mmol, 3 equiv.) was added through an addition funneldropwise while keeping it cold. The resulting mixture was stirred at 0°C. for 15 minutes, warmed to room temperature and stirred for 30minutes. The reaction was cooled to 0° C. Meanwhile a mixture of 48%aqueous HBr (24 mL, 210.0 mmol, 7 equiv.) and acetic acid (24.0 mL) wascooled to 0° C. and added to the above reaction mixture slowly at 0° C.The mixture was stirred at 0° C. for 15 minutes, warmed to roomtemperature and stirred for 30 minutes. The mixture was diluted withdiethyl ether (120 mL), washed with water (3×120 mL), dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified on an InterChim automated chromatography system (220 gSorbTech silica gel column), eluting with a gradient of 0 to 25% ethylacetate in heptanes to give compound 63-3 (4.73 g, 37% yield) as a whitesolid.

Benzyl(S)-5-((tert-butoxycarbonyl)amino)-6-oxo-7-(2,3,5,6-tetrafluorophenoxy)heptanoate(63-4): Potassium fluoride (2.6 g, 44 mmol, 4 equiv.) was added to asolution of compound 63-3 (4.7 g, 11 mmol, 1 equiv.) and2,3,5,6-tetrafluorophenol (2.0 g, 12.1 mmol, 1.1 equiv.) in DMF (50 mL).After stirring at room temperature for 18 hours, the reaction wasdiluted with ethyl acetate (150 mL), washed with saturated sodiumbicarbonate (180 mL) and saturated brine (180 mL). The organic layer wasdried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified on an InterChim automatedchromatography system (120 g RediSepRf silica gel column), eluting witha gradient of 0 to 25% ethyl acetate in heptanes to give compound 63-4(4.31 g, 77% yield) as a colorless liquid.

Benzyl (S)-5-amino-6-oxo-7-(2,3,5,6-tetrafluorophenoxy)heptanoatehydrochloride (63-5): 4M HCl in 1,4-dioxane (2.5 mL, 10.1 mmol, 1.2equiv.) was added dropwise to a solution of compound 63-4 (4.31 g, 8.39mmol, 1 equiv.) in acetonitrile (100 mL) at 0 to 5° C. The mixture waswarmed to room temperature and stirred for 6.5 hours. LCMS indicatedthat the reaction was not complete. Additional 4M HCl in 1,4-dioxane(1.7 mL, 6.7 mmol, 0.8 equiv.) was added and the mixture was stirred for18 hours at which time LCMS indicated that the reaction was complete.The mixture was concentrated under reduced pressure to give compound63-5 (3.67 g, 97% yield) as a yellowish liquid, which was usedsubsequently.

Benzyl(S)-5-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido)propanamido)-6-oxo-7-(2,3,5,6-tetrafluorophenoxy)heptanoate (63-6): Hexafluorophosphate azabenzo-triazoletetramethyluronium (HATU, 0.93 g, 2.44 mmol, 1.1 equiv.) was added to asolution of compound 8 (0.61 g, 2.22 mmol, 1 equiv.) indimethylformamide (10 mL) at room temperature. After stirring at roomtemperature for 10 minutes, compound 63-5 (1.0 g, 2.22 mmol, 1 equiv.)and N,N-diisopropylethylamine (1.2 mL, 6.66 mmol, 3 equiv.) weresequentially added. After stirring at room temperature for 18 hours, thereaction mixture was diluted with ethyl acetate (60 mL). The organiclayer was washed with water (2×50 mL), dried over sodium sulfate,filtered and concentrated under reduced pressure. The crude material waspurified on an Interchim automated chromatography system (80 g RediSepRfsilica gel column), eluting with a gradient of 0 to 50% ethyl acetate inheptanes. After concentrating the fractions under reduced pressure, theresulting solid was dried under vacuum at room temperature for 18 hoursto give compound 63-6 (0.90 g, 61% yield) as a yellowish solid.

(S)-5-((S)-2-(2-((2,6-Difluorophenyl)amino)-2-oxoacetamido)propanamido)-6-oxo-7-(2,3,5,6-tetrafluorophenoxy)heptanoicacid (63-A, Example 13): A suspension of compound 63-6 (0.63 g, 0.94mmol, 1.0 equiv.) and 10% palladium on activated carbon (63 mg, 50% wet)in tetrahydrofuran (30 mL) was hydrogenated @ 25 psi for 2 hours. LC-MSanalysis indicated that the reaction was complete. The mixture wasfiltered through Celite (15 g), which was washed with ethyl acetate(3×70 mL). The filtrates were concentrated under reduced pressure. Thecrude product was dissolved in dichloromethane (20 mL) and adsorbed ontosilica gel (10 g). The material was dry-loaded and purified on anInterchim automated system (40 g Sorbtech silica gel column), elutingwith a gradient of 0 to 8% methanol in dichloromethane. Afterconcentrating the fractions under reduced pressure, the resulting solidwas dried under vacuum at room temperature for 18 hours to give compound63-A, (Example 13) (0.45 g, 82% yield) as an off-white solid, (MassSpec. m/z=578.1 (M+H).

Example 14

2-((2,6-Difluorophenyl)amino)-2-oxoacetic acid (4) was prepared inscheme 1.

Methyl1-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido)cyclopentane-1-carboxylate(5): Compound 4 (1.00 g, 4.97 mmol, 1.0 equiv.) and1-hydroxy-7-azabenzotriazole (0.81 g, 5.97 mmol, 1.2 equiv.) weredissolved in anhydrous dichloromethane (50.0 mL).1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.93 g,5.97 mmol, 1.2 equiv.) and triethylamine (2.01 g, 19.89 mmol, 4.0equiv.) were added sequentially and the mixture was stirred for 10minutes. Methyl 1-aminocyclopentane-1-carboxylate hydrochloride (0.89 g,4.97 mmol, 1.0 equiv.) was added. After stirring at room temperature for4 days, the reaction mixture was washed with water (50 mL. The aqueouslayer was extracted with dichloromethane (50 mL). The combined organiclayers were dried over sodium sulfate and concentrated under reducedpressure. The residue was dissolved in dichloromethane (10 mL), adsorbedonto Celite and purified on an InterChim automated chromatography system(RediSep silica gel column, 80 g), eluting with a gradient of 0 to 50%ethyl acetate in heptanes to give compound 5 (0.356 g, 21% yield) as awhite solid.

1-(2-((2,6-Difluorophenyl)amino)-2-oxoacetamido)cyclopentane-1-carboxylicacid (6): Lithium hydroxide (52.8 mg, 2.206 mmol, 2.4 equiv.) in water(2.2 mL) was added to a solution of compound 5 (0.300 g, 0.919 mmol, 1.0equiv.) in tetrahydrofuran (10.0 mL). The mixture was stirred at roomtemperature for 3 hours. The reaction was cooled to 10° C., diluted withwater (20 mL) and adjusted to pH=2 with aqueous 1N HCl. The resultantsolid was filtered and washed with water. The solid was dried undervacuum at 40° C. for 18 hours to give compound 6 (0.160 g, 56% yield) asa white solid.

Benzyl (S)-4-(1-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido)cyclopentane-1-carboxamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoate (62-1):[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate (261 mg, 1.1 equiv.) and compound 58-5 (272 mg,0.624 mmol, 1.0 equiv.) were sequentially added to a solution ofcompound 6 (0.195 g, 0.624 mmol, 1.0 equiv.) in anhydrousdimethylformamide (3.0 mL). After stirring for 20 hours, the mixture waspoured into saturated sodium bicarbonate (50 mL) and extracted withethyl acetate (2×80 mL). The combined organic layers were washed withsaturated brine (50 mL), dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified on anInterChim automated chromatography system (Sorbtech silica gel column,2×12 g in series), eluting with a gradient of 0 to 50% ethyl acetate inheptanes to give compound 62-1 (0.178 g, 41% yield) as a white solid.

(S)-4-(1-(2-((2,6-Difluorophenyl)amino)-2-oxoacetamido)cyclopentane-1-carboxamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoicacid (62-A, Example 14): A mixture of compound 61-3 (0.178 g, 0.257mmol, 1.0 equiv.) and 10% Pd/C (50 mg, 50% wet) in tetrahydrofuran (15mL) was hydrogenated @ 22 psi for 2 hours. The reaction mixture wasfiltered through Celite, which was washed with tetrahydrofuran (25 mL).The filtrate was concentrated under reduced pressure. The residue waspurified on an InterChim automated chromatography system (Sorbtechsilica gel column, 12 g), eluting with a gradient of 0 to 5% methanol indichloromethane to give an oily solid. The residue was dissolved inacetonitrile and water, frozen at −78° C. and lyophilized to dryness togive compound 62-A, (Example 14) (85 mg, 55% yield) as a white solid,(Mass Spec. m/z=604.2 (M+H).

Example 15

Benzyl (S)-6-bromo-4-((tert-butoxycarbonyl)amino)-5-oxohexanoate (58-3):Isobutyl chloroformate (5.84 mL, 45.0 mmol, 1.5 equiv.) was addeddropwise to a solution of(S)-5-(benzyloxy)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoic acid(58-1) (10.12 g, 30.0 mmol, 1 equiv.) and N-methylmorpholine (5.28 mL,48 mmol, 1.6 equiv.) in THF (100 mL) at −10° C. After stirring at −10°C. for 20 minutes, the reaction was filtered through celite andconcentrated under reduced pressure to give the mixed anhydride (12.7 g)as a colorless oil, which was used subsequently.

Diazomethane preparation: A solution ofN-methyl-N′-nitroso-p-toluenesulfonamide (Diazald®, 19.28 g, 90.0 mmol,1 equiv.) in diethyl ether (66 mL) was added through an addition funnelto a mixture of potassium hydroxide (15.12 g, 270 mmol, 3 equiv.) inethanol (30 mL) and water (26 mL) in an oil bath at 65° C. The receivingflask to collect the ethereal solution of diazomethane was cooled in anice-bath and the Diazald® solution was added at such a rate as thatallowed for a dropwise distillation into the receiving flask. When allof the Diazald® solution had been added, additional diethyl ether (10mL) was added through the addition funnel until the distillate was clear(no remaining diazomethane). After cooling to room temperature, themixture in the distillation flask was quenched slowly with acetic aciduntil the yellow color disappeared.

A solution of freshly prepared mixed anhydride above (12.7 g, 29.0 mmol,1 equiv.) in diethyl ether (110 mL) was placed in a clear-seal jointflask and cooled to 0° C. in an ice bath. The freshly prepareddiazomethane ethereal solution (˜90.0 mmol, 3 equiv.) was added throughan addition funnel dropwise while keeping it cold. The resulting mixturewas stirred at 0° C. for 15 minutes, warmed to room temperature andstirred for 30 minutes. The reaction was cooled to 0° C. Meanwhile amixture of 48% aqueous HBr (24 mL, 210.0 mmol, 7 equiv.) and acetic acid(24.0 mL) was cooled to 0° C. and added to the above reaction mixtureslowly at 0° C. The mixture was stirred at 0° C. for 15 minutes, warmedto room temperature and stirred for 30 minutes. The mixture was dilutedwith diethyl ether (120 mL), washed with water (3×120 mL), dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified on an InterChim automated chromatography system(220 g SorbTech silica gel column), eluting with a gradient of 0 to 30%ethyl acetate in heptanes to give compound 58-3 (7.12 g, 57% yield) as awhite solid.

Benzyl (S)-4-((tert-butoxycarbonyl)amino)-5-oxo-6-((2-(trifluoromethyl)pyrimidin-4-yl)oxy)hexanoate (66-1): Potassium fluoride (1.121 g, 19.29mmol, 4 equiv.) was added to a solution of compound 58-3 (2.0 g, 4.83mmol, 1 equiv.) and 2-(trifluoromethyl)pyrimidin-4-ol (0.871 g, 5.31mmol, 1.1 equiv.) in DMF (20 mL). After stirring at room temperature for20 hours, the reaction was diluted with ethyl acetate (250 mL), washedwith saturated sodium bicarbonate (300 mL) and saturated brine (300 mL).The organic layer was dried over sodium sulfate (100 g), filtered andconcentrated under reduced pressure. The residue was purified on anInterChim automated chromatography system (80 g SorbTech silica gelcolumn, sample wet loaded in dichloromethane (10 mL)), eluting with agradient of 0 to 30% ethyl acetate in heptanes to give compound 66-1(1.805 g, 75% yield) as a colorless viscous oil.

Benzyl (S)-4-amino-5-oxo-6-((2-(trifluoromethyl)pyrimidin-4-yl)oxy)hexanoate hydrogen chloride (66-2): 4M HCl in 1,4-dioxane (1.8 mL, 7.18mmol, 2.0 equiv.) was added dropwise to a solution of compound 66-1(1.78 g, 3.6 mmol, 1 equiv.) in acetonitrile (70 mL) at 5° C. Themixture was warmed to room temperature and stirred for 20 hours. Themixture was concentrated under reduced pressure. Methanol (100 mL) wasadded and the mixture was concentrated under reduced pressure. Theresidue was dried under vacuum at room temperature for 1 hour. The solidwas diluted with diethyl ether (2×100 mL) and decanted. The residue wasdried under vacuum at room temperature for 2 hours to give compound 66-2(1.331 g, 85% yield) as an off-white solid.

Benzyl (S)-4-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido)propanamido)-5-oxo-6-((2-(trifluoromethyl)pyrimidin-4-yl)oxy)hexanoate(66-3): EDC.HCl (0.583 g, 3.0 mmol, 1.1 equiv.) was added to asuspension of compound 8 (0.752 g, 2.8 mmol, 1.0 equiv.) and HOAt (0.452g, 3.32 mmol, 1.2 equiv.) in acetonitrile (25 mL). After stirring themixture at room temperature for 10 minutes, compound 66-2 (1.2 g, 2.8mmol, 1.0 equiv.) and triethylamine (0.771 mL, 5.53 mmol, 2.0 equiv.)were sequentially added and the mixture was stirred at room temperaturefor 16 hours. The reaction mixture was diluted with ethyl acetate (250mL) and washed with saturated sodium bicarbonate (250 mL) and saturatedbrine (250 mL). The sodium bicarbonate layer was extracted withadditional ethyl acetate (300 mL). This ethyl acetate layer was washedwith the initial saturated brine solution. The combined organic layerswere dried over sodium sulfate (100 g), filtered and concentrated underreduced pressure. The crude material was purified on an Interchimautomated chromatography system (40 g, RediSep silica gel column, sampledry loaded using celite (4 g)), eluting with a gradient of 0 to 50%ethyl acetate in heptanes to give desired product (66-3) (1.069 g, 59%yield) as an off-white solid.

(S)-4-((S)-2-(2-((2,6-Difluorophenyl)amino)-2-oxoacetamido)propanamido)-5-oxo-6-((2-(trifluoromethyl)pyrimidin-4-yl)oxy)hexanoicacid (66-A, Example 15): A suspension of compound 66-3 (1.069 g, 1.64mmol, 1 equiv.) and 10% palladium on carbon (110 mg, 50% wet) intetrahydrofuran (30 mL) was hydrogenated @ 25 psi for 2.5 hours at roomtemperature. Analysis by LC-MS indicated 20% conversion of the startingmaterial to product was observed. The reaction mixture was purged withnitrogen gas for 5 minutes and additional 10% palladium on carbon (110mg, 50% wet) was added and purged with nitrogen gas for additional 5minutes and hydrogenated @ 25 psi for additional 3 hours at roomtemperature. The suspension was filtered through celite (50 g). Thecelite bed was washed with ethyl acetate (250 mL). The filtrate wasconcentrated under reduced pressure and the crude material was purifiedon an Interchim automated chromatography system (40 g, RediSep silicagel column; sample dry loaded using celite (4 g) eluting with 0 to 10%methanol in dichloromethane to give desired compound 66-A (as twofractions 410 mg, >95.9% purity by HPLC and fraction; 235 mg, 94.8%purity by HPLC). Due to the traces amount of impurities in ¹H-NMR, thecompound 66-A (410 mg) was triturated with dichloromethane (2 mL),filtered and washed with dichloromethane (2 mL). The product was driedunder vacuum at 40° C. for 16 hours to give compound 66-A, (Example 15)(0.336 g, 36% yield, 98.9% purity by HPLC) as a white solid, (Mass Spec.m/z=562.1 (M+H).

Example 16

Benzyl (S)-6-bromo-4-((tert-butoxycarbonyl)amino)-5-oxohexanoate (58-3):The procedure for the preparation of compound 58-3 was shown in Scheme14.

Benzyl (S)-4-((tert-butoxycarbonyl)amino)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoate (58-4): Potassium fluoride (2.46 g, 44.4 mmol, 4equiv.) was added to a solution of freshly prepared compound 58-3 (4.48g, 10.6 mmol, 1 equiv.) and 2,3,5,6-tetrafluorophenol (1.94 g, 11.7mmol, 1.1 equiv.) in anhydrous DMF (44 mL). After stirring at roomtemperature for 18 hours, the reaction was diluted with ethyl acetate(120 mL), washed with saturated sodium bicarbonate (120 mL) andsaturated brine (120 mL). The organic layer was dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified on an InterChim automated chromatography system (120 gSorbTech silica gel column), eluting with a gradient of 0 to 25% ethylacetate in heptanes to give compound 58-4 (3.98 g, 77% yield) as a clearliquid.

Benzyl (S)-4-amino-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoatehydrochloride (58-5): 4M HCl in 1,4-dioxane (2.2 mL, 8.7 mmol, 1.2equiv.) was added dropwise to a solution of compound 58-4 (3.6 g, 7.2mmol, 1 equiv.) in acetonitrile (80 mL) at 0 to 5° C. The mixture waswarmed to room temperature and stirred for 6.5 hours. LCMS indicatedthat the reaction was not complete. Additional 4M HCl in 1,4-dioxane(1.5 mL, 5.8 mmol, 0.8 equiv.) was added and the mixture was stirred for18 hours at which time LCMS indicated that the reaction was complete.The mixture was concentrated under reduced pressure to give compound58-5 (2.87 g, 91% yield) as an orange liquid, which was usedsubsequently.

Benzyl(S)-4-(2-(7-chloro-1-oxoisoquinolin-2(1H)-yl)acetamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoate(67-1): Hexafluorophosphate azabenzo-triazole tetramethyluronium (HATU,0.96 g, 2.52 mmol, 1.1 equiv.) was added to a solution of compound 15(0.54 g, 2.3 mmol, 1 equiv.) in dimethylformamide (10 mL) at roomtemperature. After stirring at room temperature for 10 minutes, compound58-5 (1.0 g, 2.29 mmol, 1 equiv.) and N,N-diisopropylethylamine (1.2 mL,6.87 mmol, 3 equiv.) were sequentially added. After stirring at roomtemperature for 18 hours, the reaction mixture was diluted with ethylacetate (80 mL). The organic layer was washed with water (2×40 mL),dried over sodium sulfate, filtered and concentrated under reducedpressure. The crude material was purified on an Interchim automatedchromatography system (80 g SorbTech silica gel column), eluting with agradient of 0 to 50% ethyl acetate in heptanes. After concentrating thefractions under reduced pressure, the resulting solid was dried undervacuum at room temperature for 3 hours to give compound 67-1 (0.79 g,56% yield) as an off-white solid.

(S)-4-(2-(7-Chloro-1-oxoisoquinolin-2(1H)-yl)acetamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoicacid (67-A, Example 16): 1M Lithium hydroxide (0.64 mL, 0.64 mmol, 0.95equiv.) was added to a solution of compound 67-1 (0.42 g, 0.67 mmol, 1equiv.) in the mixture of 1,4-dioxane (12 mL) and water (3 mL) at 0° C.and stirred for 10 minutes. The reaction mixture was concentrated underreduced pressure at room temperature. The residue was diluted with water(5 mL) and extracted with diethyl ether (15 mL) to remove any organicimpurities. The aqueous layer was adjusted to pH 3 with 1N HCl (˜1.0 mL)and extracted with ethyl acetate (3×50 mL). The combined organic layerswere dried over sodium sulfate, filtered and concentrated under reducedpressure. The crude product was dissolved in the mixture ofdichloromethane (7 mL) and methanol (1 mL), adsorbed onto silica gel (10g) and purified on an Interchim automated system (40 g RediSepRf silicagel column), eluting with a gradient of 0 to 8% methanol indichloromethane. After concentrating the fractions under reducedpressure, the resulting solid was dried under vacuum at room temperaturefor 4 hours to give compound 67-A, (Example 16) (0.30 g, 86% yield,97.3% purity by HPLC) as a white solid, (Mass Spec. m/z=529.1 (M+H).

Examples 17-42

Compounds 68-A through 68-ZZ were prepared by the process outlined inthe above scheme.

68-A Ex. 17

m/z = 546.2 (M + H) (S)-4-((S)-2-(2-((4- fluorophenyl)amino)-2-oxoacetamido)propanamido)-5- oxo-6-(2,3,5,6- tetrafluorophenoxy)hexanoicacid 68-B Ex. 18

m/z = 546.2 (M + H) (S)-4-((S)-2-(2- ((3fluorophenyl)amino)-2-oxoacetamido)propanamido)-5- oxo-6-(2,3,5,6- tetrafluorophenoxy)hexanoicacid 68-C Ex. 19

m/z = 542.2 (M + H) (S)-4-((S)-2-(2-((4- methylphenyl)amino)-2-oxoacetamido)propanamido)-5- oxo-6-(2,3,5,6- tetrafluorophenoxy)hexanoicacid 68-D Ex. 20

m/z = 542.2 (M + H) (S)-4-((S)-2-(2-((3- methylphenyl)amino)-2-oxoacetamido)propanamido)-5- oxo-6-(2,3,5,6- tetrafluorophenoxy)hexanoicacid 68-E Ex. 21

m/z = 542.2 (M + H) (S)-4-((S)-2-(2-((2- methylphenyl)amino)-2-oxoacetamido)propanamido)-5- oxo-6-(2,3,5,6- tetrafluorophenoxy)hexanoicacid 68-F Ex. 22

m/z = 558.2 (M + H) (S)-4-((S)-2-(2-((2- methyoxyphenyl)amino)-2-oxoacetamido)propanamido)-5- oxo-6-(2,3,5,6- tetrafluorophenoxy)hexanoicacid 68-G Ex. 23

m/z = 558.2 (M + H) (S)-4-((S)-2-(2-((3- methyoxyphenyl)amino)-2-oxoacetamido)propanamido)-5- oxo-6-(2,3,5,6- tetrafluorophenoxy)hexanoicacid 68-H Ex. 24

m/z = 558.2 (M + H) (S)-4-((S)-2-(2-((4- methyoxyphenyl)amino)-2-oxoacetamido)propanamido)-5- oxo-6-(2,3,5,6- tetrafluorophenoxy)hexanoicacid 68-I Ex. 25

m/z = 543.2 (M + H) (S)-4-((S)-2-(24(5-methylpyridin- 2-yl)amino)-2-oxoacetamido)propanamido)-5- oxo-6-(2,3,5,6- tetrafluorophenoxy)hexanoicacid 68-J Ex. 26

m/z = 596.1 (M + H) (S)-5-oxo-4-((S)-2-(2-oxo-2-((3-(trifluoromethyl)phenyl)amino) acetamido)propanamido)-6-(2,3,5,6-tetrafluorophenoxy) hexanoic acid 68-K Ex. 27

m/z = 596.1 (M + H) (S)-5-oxo-4-((S)-2-(2-oxo-2-((4-(trifluoromethyl)phenyl)amino) acetamido)propanamido)-6-(2,3,5,6-tetrafluorophenoxy) hexanoic acid 68-L Ex. 28

m/z = 654.2 (M + H) benzyl(S)-4-((S)-2-(2-((2,6-difluorophenyl)amino)-2- oxoacetamido)propanamido)-5- oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoate 68-M Ex. 29

m/z = 563.1 (M + H) (S)-4-((S)-2-(2-((5-chloropyridin- 2-yl)amino)-2-oxoacetamido)propanamido)-5- oxo-6-(2,3,5,6- tetrafluorophenoxy)hexanoicacid 68-N Ex. 30

m/z = 570.2 (M + H) (S)-4-((S)-2-(2-((4- acetylphenyl)amino)-2-oxoacetamido)propanamido)-5- oxo-6-(2,3,5,6- tetrafluorophenoxy)hexanoicacid 68-O Ex. 31

m/z = 596.2 (M + H) (S)-4-((S)-2-(2-((3-(1H-tetrazol-5-yl)phenyl)amino)-2- oxoacetamido)propanamido)-5- oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid 68-P Ex. 32

m/z = 553.1 (M + H) (S)-4-((S)-2-(2-((2- cyanophenyl)amino)-2-oxoacetamido)propanamido)-5- oxo-6-(2,3,5,6- tetrafluorophenoxy)hexanoicacid 68-Q Ex. 33

m/z = 630 (M + H) (S)-6-((2,6- bis(trifluoromethyl)pyrimidin-4-yl)oxy)-4-((S)-2-(2-((2,6- difluorophenyl)amino)-2-oxoacetamido)propanamido)-5- oxohexanoic acid 68-R Ex. 34

m/z = 612.1 (M + H) (S)-5-oxo-4-((S)-2-(2-oxo-2-((4-(trifluoromethoxy)phenyl)amino) acetamido)propanamido)-6-(2,3,5,6-tetrafluorophenoxy) hexanoic acid 68-S Ex. 35

m/z = 579.1 (M + H) (S)-5-oxo-4-((S)-2-(2-oxo-2-(quinolin-3-ylamino)acetamido) propanamido)-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid 68-T Ex. 25

m/z = 578.2 (M + H) (S)-4-((S)-2-(2-(naphthalen-1- ylamino)-2-oxoacetamido)propanamido)-5- oxo-6-(2,3,5,6- tetrafluorophenoxy)hexanoicacid 68-U Ex. 36

m/z = 579.1 (M + H) (S)-5-oxo-4-((S)-2-(2-oxo-2- (quinolin-8-ylamino)acetamido)propanamido)- 6-(2,3,5,6- tetrafluorophenoxy)hexanoicacid 68-V Ex. 37

m/z = 529.1 (M + H) (S)-5-oxo-4-((S)-2-(2-oxo-2- (pyridin-4-ylamino)acetamido)propanamido)- 6-(2,3,5,6- tetrafluorophenoxy)hexanoicacid 68-W Ex. 38

m/z = 564.1 (M + H) (R)-4-((S)-2-(2-((2,6- difluorophenyl)amino)-2-oxoacetamido)propanamido)-5- oxo-6-(2,3,5,6- tetrafluorophenoxy)hexanoicacid 68-X Ex. 39

m/z = 529.1 (M + H) (S)-5-oxo-4-((S)-2-(2-oxo-2- (pyridin-2-ylamino)acetamido)propanamido)- 6-(2,3,5,6- tetrafluorophenoxy)hexanoicacid 68-Y Ex. 40

m/z = 529.1 (M + H) (S)-5-oxo-4-((S)-2-(2-oxo-2- (pyridin-3-ylamino)acetamido)propanamido)- 6-(2,3,5,6- tetrafluorophenoxy)hexanoicacid 68-Z Ex. 41

m/z = 558 (M + H) (S)-4-((S)-2-(2-((4,6-dimethylpyrimidin-2-yl)amino)-2- oxoacetamido)propanamido)-5-oxo-6-(2,3,5,6- tetrafluorophenoxy)hexanoic acid 68-ZZ Ex. 42

m/z = 530.1 (M + H) (S)-5-oxo-4-((S)-2-(2-oxo-2- (pyrimidin-2-ylamino)acetamido)propanamido)- 6-(2,3,5,6- tetrafluorophenoxy)hexanoicacid

Example 43

N¹—((S)-1-(((S)-6-((Benzyloxy)amino)-2,6-dioxo-1-(2,3,5,6-tetrafluorophenoxy)hexan-3-yl)amino)-1-oxopropan-2-yl)-N²—(2,6difluorophenyl)oxalamide: 80-1

Diisopropylethylamine (0.47 ml, 0.34 g, 2.66 mmol, 3.0 equiv) was addeddropwise to a solution of compound 58-A (0.50 g, 0.89 mmol, 1.0 equiv)and O-benzylhydroxylamine (0.17 g, 1.06 mmol, 1.2 equiv) in DMF (15 ml)at 0° C. HATU (1.24 g, 1.95 mmol, 1.5 equiv) was added portionwise andthe reaction mixture gradually warmed up to room temperature overnight.LC-MS analysis indicated that the reaction was complete. The reactionmixture was poured into saturated sodium bicarbonate (100 mL) andextracted with ethyl acetate (2×70 mL). The combined organic layers werewashed with 10% lithium chloride (100 mL), saturated brine (100 mL),dried over sodium sulfate and concentrated under reduced pressure. Thecrude product was purified on a Büchi automatic chromatography system(40 g SorbTech silica gel column), eluting with a gradient of 30 to 60%ethyl acetate in heptanes to give 80-1 (0.44 g, 74% yield) as a whitesolid, (Mass Spec. m/z=669.2 (M+H).

N¹—(2,6-difluorophenyl)-N²—((S)-1-(((S)-6-(hydroxyamino)-2,6-dioxo-1-(2,3,5,6-tetrafluorophenoxy)hexan-3-yl)amino)-1-oxopropan-2-yl)oxalamide

80-2. 80-1 (0.44 g, 0.65 mmol, 1.0 equiv) and 10% palladium on carbon(88 mg, 50% wet) in THF (20 ml) was hydrogenated at 25 psi for 2 hours.Upon completion, the reaction mixture was filtered through Celite (15 g)which was washed with THF (120 mL). The filtrate was concentrated underreduced pressure. The crude product was purified on a Büchi automaticchromatography system (40 g SorbTech silica gel column), eluting with agradient of 0 to 5% methanol in dichloromethane to give 80-2 (0.32 g,85% yield, 90% purity) as a yellow solid. The product was furtherpurified on a Büchi automatic chromatography system (30 g RediSep RfGold Reversed-phase C18 column), eluting with a gradient of 0 to 30%acetonitrile in water to give 80.2 (0.18 g, 48% yield, 95% purity) as anoff-white solid, (Mass Spec. m/z=579.2 (M+H).

Example 44 Assay for the Inhibition of Caspase Enzyme Activity andDetermination of IC₅₀ Values

Human caspases were purchased from Enzo Biosciences and used accordingto the manufacturer's instructions. An exemplary caspase assay, forCaspase-1, is provided below:

Caspase-1 Assay

Caspase-1 was diluted to 10 U/μl in assay buffer consisting of 50 mMHEPES, pH 7.4, 100 mM NaCl, 0.1% CHAPS, 1 mM EDTA, 10% glycerol and 10mM DTT.

Reaction Conditions:

45 μl of assay buffer was added into ½ volume microtiter plate. Theplate was allowed to equilibrate to assay temperature. 5 μl of Caspase-1(10U/μl) was added to each appropriate well. Two 2 blank wellscontaining assay buffer alone without Caspase-1 were included on theplate.

The reaction was started by the addition of 50 μl Ac-YVAD-pNA substrate,for a final substrate concentration of 200 M. The reaction wascontinuously monitored at 405 nm. The data was graphed as OD_(405 nm) vstime, and the slope was determined over the linear portion of the curve.The rates in OD/min were converted to substrate/min using an extinctioncoefficient for p-nitroaniline of 10,500M−1 cm−1, and were adjusted forpathlength of sample.

Enzymatic assays were conducted for Caspase-3, 6 and 7 activityaccording to the manufacture's instructions. Caspase enzyme inhibitionIC₅₀ data for selected compounds as prepared according to methodsdescribed herein is presented below.

TABLE 1 Example Caspase 1 Caspase 3 Caspase 6 Caspase 7 IDN-7314 A A A A1 B D D D 2 B D D D 3 C D D D 4 B D D D 5 C D D D 6 A D D D 7 B D D D 8C D D D 9 A D D D 10 A D D D 11 A D D C 12 A D D D 13 B D D D 14 A C C C15 A D D D 16 A D D D 17 A D D D 18 A D D D 19 A D D D 20 A D D D 21 A DD D 22 A D D D 23 A D D D 24 A D D D 25 A D D D 26 A D D D 27 A D D D 28A D D D 29 A D D D 30 A D D D 31 A D D D 32 A D D D 33 A D D D 34 A D DD 35 A D D D 36 A D D D 37 A D D D 38 A D D D 39 A D D D 40 A D D D 41 AD D D 42 A D D D KEY: A ≤ 10 nM; B > 10 nM ≤ 100 nM; C > 100 nM < 1000nM; D ≥ 1000 nM

Example 45 Assay for the Activity and Selectivity Determination inCell-Based Models

Compounds in the present invention were tested in THP-1 cells, a humanmonocyte cell line, to assess the inhibition of the inflammatorycytokine interleukin-1β. THP-1 cells (ATCC TIB-202) were grown inculture and seeded in 96 well plates at a concentration of 200,000 cellsper well with a total volume of 150 μL. Plated cells were incubatedovernight at 37 degrees C. under an atmosphere of 5% CO₂. Media wasremoved from cells which were washed with PBS. Test compounds werediluted in DMSO stock solution and serially diluted appropriately forinitial screening and IC₅₀ determinations. LPS in serum free media (140μL of 1 μg/μL) was added to each well to stimulate IL-1β production.IL-1β was measured by ELISA assay kit (R&D Systems) per themanufacturers instructions. The pan caspase inhibitor, IDN-7314, wasincluded in cell-based screening and IC₅₀ assays as a referencecompound.

Table 2 below provides selected THP 1 screening data at 10 micromolar.

TABLE 2 Percent Inhibition Example of IL1-β IDN-7314 A 1 B 2 B 3 C 4 B 5C 6 A 7 B 8 C 9 A 10 A 11 A 12 A 13 B 14 A 15 A 16 A 17 A 18 A 19 A 20 AKEY: A > 90%; B ≤ 90% > 50%; C ≤ 50% > 25%

IC₅₀ values for the inhibition of IL-1β in THP 1 cells were determinedfrom dose response studies. An example of a dose response study in THP 1cells is shown in FIG. 1.

Compounds of the present invention were evaluated in Jurkat cells, ahuman T-lymphocyte cell line, to evaluate compounds ability to inhibitapoptotic cell death. Jurkat cells, Clone E6-1 (ATCC TIB-152) were grownin culture maintain a cell density between 0.5-2 million cells/mL. Cellswere tested for viability and countion with typan blue stain before use.Test compounds were added to 96 well plates and Jurkat cells were addedat a concentration of approximately 100,000 cells per well and mixedthoroughly by action of pipetting. Plated cells were incubated for 1hour at 37 degrees C. under an atmosphere of 5% CO₂. Anti-Fas antibodywas added and mixed by pipet action. Plates were incubated for 20 hoursat 37 degrees C. under an atmosphere of 5% CO₂. 10 microliters of thawedWST-8 solution was added to each well and incubated for 4 hours.Absorbance was measured at 450 nM and control reading at 630 nM using aSpectraMax ID5 plate reader. Apoptotic cell death is executed bycaspases 3, 7 and 6. Compounds that lack activity against these caspaseswill not prevent the death of Jurkat cells and is a functional test ofselectivity for inflammatory over apoptotic caspases.

Table 3 lists data of selected examples screened at a concentration of10 micromolar.

A pan-caspase inhibitor, IDN-7314, a potent inhibitor of both theinflammatory and apoptotic caspases, was included as a referencecompound in this cell-based assay of apoptosis.

TABLE 3 % Prevention of Fas - induced Jurkat cell Example apoptosis at10 micromolar IDN-7314 A 1 D 2 D 3 D 4 D 5 D 6 D 7 D 8 D 9 D 10 D 11 D12 D 13 D 14 D 15 D 16 D 17 D 18 D 19 D 20 D KEY: A > 90%; B ≤ 90% >50%; C ≤ 50% > 25%; D ≤ 10%

IC₅₀ values to protect against Fas induced apoptosis and improvesurvival of Jurkat cells were determined from dose response studies. Anexample of a dose response study to Fas induced apoptosis in Jurkatcells is shown in FIG. 2.

Example 46 Assay for the Activity in In Vivo Models of Inflammation andCytokine Production

Compounds of the present invention were tested in a mouse in vivo modelof peritoneal inflammation (peritonitis). Mice were treated withintraperotonial injection of bacterial endotoxin, (LPS). After 1 hour,test compounds were administered by IP injection. After an additionalhour, adenosine triphosphate (ATP) was administered by IP injection tofurther induce the production of the inflammatory cytokines, IL-1β andIL 18. After 0.5 hours, peritoneal lavage fluid was collected andanalyzed for IL-1β and IL 18. An inhibitor of the NLRP 3 inflammasome,MCC950, was administered by IP injection and included as a referencetest compound. The compound of Example 6 of the present inventionafforded statistically significant inhibition of the in vivo productionof both IL-1β and IL 18. IL18 levels were determined by a commerciallyavailable ELISA kit following the manufacture's instructions FIG. 3.

Example 47 Assay for the Activity in In Vivo Models GastrointestinalDisease: Ulcerative Colitis

Compounds of the present invention were tested by oral administration ina rodent model of ulcerative colitis (UC). Ulcerative colitis wasinduced in Sprague-Dawley rats by instillation of 48 mg/kgtrinitrobenzene disulfonic acid, (TNBS), through the rectum. Testingincluded 4 active treatment groups and one vehicle control group.

Effect of TNBS-induced UC in vehicle treated control group, (Group 1):

Rats were administered of 0.5% vehicle carboxy methylcellulose, (CMC),twice daily starting 24 hours after the instillation of TNBS. Thisresulted in an 17% weight loss by DAY 7, relative to DAY 0 weights inthe control group.

At the termination of the study on DAY 7, the average colon weight inthe diseased rats was 5.904±2.208 g, the average colon length was11.0±1.4 cm and the average distal colon width was 3.1±1.0 cm. Severeadhesions involving multiple intestinal loops, severe strictureresulting in proximal colon distension, ulcers of 6.4±0.4 cm in length,and colonic wall thickness of 3.5±0.8 mm combined to yield an overallcolonic score of 11.5±0.8 in the diseased rats. Histological evaluationof the distal colon section revealed subacute inflammation of themucosa, submucosa, and less frequently, colon wall and serosa; mucosalnecrosis/gland loss; erosions; submucosa edema; and epithelialhyperplasia. Subacute inflammation (sub/mucosal and transmural/serosalwere graded separately) was characterized by infiltration andaggregation of neutrophils, eosinophils, lymphocytes, plasma cells, andmacrophages. Mucosal necrosis was characterized by damage to, necrosisof, or complete loss of colonic glands. Erosions were characterized bycoagulative necrosis or loss of surface epithelium superficial to themuscularis mucosae. Submucosal edema was characterized by expansion ofthe submucosa by clear space or pale eosinophilic fluid, variablyaccompanied by dilation of lymphatic vessels and similar edematousexpansion of the lamina propria. Epithelial hyperplasia wascharacterized by elongation of colonic glands and increased numbers ofepithelial mitotic figures.

Effect of therapeutic treatment with positive control: Prednisolone(Group 2):

Once daily oral administration of 10 mg/kg prednisolone starting 24hours after the instillation of 48 mg/kg TNBS through the rectumresulted in improved animal health by DAY 4 as reflected by increasedbody weight. All measured colon parameters were significantly improvedresulting in a statistically significant 67% reduction in the overallcolonic score and an average 40% inhibition of the histologicalparameters.

Effect of therapeutic treatment with the compound of Example 6 (Groups3-5):

Twice daily oral administration of the compound of Example 6 suspensionin 0.5% CMC had a statistically significant effect on animal health, asdetermined by effect on animal weights, at all dose levels, Groups 3-5.The lowest dose (Group 3, 10 mg/kg/dose) had body weights significantlyimproved beginning on DAY 4. The mid-dose group (Group 4, 30 mg/kg/dose)and high dose group (Group 5, 100 mg/kg/dose) had statisticallysignificantly improved body weights starting on DAY 5, as shown in Table4 and FIG. 4.

All dose groups achieved statistically significant improvement inoverall colonic score. The mid dose (Group 4, 30 mg/kg/dose) resulted inthe best improvement in gross colon parameters (40% reduction in overallcolonic score), Table 4 and FIG. 4.

All dose groups achieved statistically significant improvement of SUMscores of colon histological parameters, see, Table 4 and FIG. 4.

TABLE 4 Effect of disease and treatment on average weight loss STUDY DAYGroup Statistic −5 −1 0 1 2 3 4 5 6 7 1 Mean 222 251 236 231 220 211 205202 199 195 (TNBS) SD 6 10 10 12 13 13 14 13 12 13 2 Mean 222 249 235232 221 223 223 227 227 229 Prednis SD 5 11 10 10 12 17 19 22 24 23p-value 1.00 0.72 0.89 0.77 0.94 0.10 0.03 0.006 0.004 0.0008 3 Mean 222256 241 236 223 218 218 222 227 228 10 mpk SD 5 10 9 8 10 12 12 15 21 24p-value 1.00 0.25 0.19 0.27 0.59 0.22 0.05 0.004 0.002 0.001 4 Mean 222248 234 228 215 214 216 218 220 223 30 mpk SD 5 4 3 4 9 16 23 26 32 35p-value 1.00 0.41 0.57 0.46 0.31 0.70 0.21 0.09 0.07 0.03 5 Mean 222 246232 231 219 213 217 220 222 225 100 mpk SD 5 11 11 11 13 18 21 24 27 28p-value 1.00 0.38 0.40 0.98 0.80 0.78 0.17 0.05 0.02 0.01 Significance(p-value) vs Group 1 was calculated by Student's t-Test.

TABLE 5 Effect of disease and treatment on average colon histology:Subacute Necrosis, Subacute Inflammation, Mucosal/ Inflammation,Mucosal/ Gland Erosion/ Edema, Hyperplasia, Transmural/ SUM GroupStatistic Submucosal Loss Ulceration Submucosal Epithelial Serosal Score1 Mean 4.7 5.0 5.0 3.6 5.0 4.4 27.7 SD 0.9 0.0 0.0 1.3 0.0 1.3 2.2 2Mean 3.5 2.9 2.9 2.3 2.9 2.8 16.3 SD 1.3 1.6 1.6 0.8 1.3 1.6 5.9 p-value0.03 0.0006 0.0006 0.01 7 × 10⁻⁵ 0.02 2 × 10⁻⁵ 3 Mean 4.3 4.0 4.0 3.23.4 3.9 19.3 SD 0.8 1.2 1.2 1.4 1.8 1.3 3.4 p-value 0.33 0.01 0.01 0.510.01 0.39 4 × 10⁻⁶ 4 Mean 3.9 3.4 3.4 2.6 3.1 3.2 17.6 SD 1.4 2.0 2.00.8 1.8 1.5 7.2 p-value 0.16 0.02 0.02 0.05 0.004 0.07 0.0005 5 Mean 3.93.6 3.6 3.0 3.0 3.4 17.5 SD 1.7 1.8 1.8 1.4 1.9 2.0 7.4 p-value 0.200.02 0.02 0.33 0.004 0.19 0.0006

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the subject matter. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations and/or methods ofuse provided herein, can be made without departing from the spirit andscope thereof. U.S. patents and publications referenced herein areincorporated by reference.

The embodiments described above are intended to be merely exemplary, andthose skilled in the art will recognize, or will be able to ascertainusing no more than routine experimentation, numerous equivalents ofspecific compounds, materials, and procedures. All such equivalents areconsidered to be within the scope of the claimed subject matter and areencompassed by the appended claims.

What is claimed is:
 1. A compound having formula I:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein X and Y are selected asfollows: i) X is C═O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, —R^(a)OR^(b), or —R^(a)N(R^(c))(R^(d)); or ii) X is —O—, or—N(R^(c))—; Y is hydrogen, —C(O)R^(d), alkyl, cycloalkyl, heterocyclyl,aryl, heteroaryl; Y is optionally substituted with one to three groupsQ¹; R³, Y¹, Y² and Y³ are selected as follows: i) Y¹ together with R³forms an optionally substituted saturated or unsaturated bicyclic ringB, where substituents on ring B, when present, are selected from one tothree groups Q¹; Y² is absent, hydrogen or alkyl; and Y³ is absent,hydrogen or alkyl; or ii) R³ is hydrogen or alkyl; Y¹ and Y² togetherare ═O; and Y³ is —N(Z¹)(Z²); X, Y, R³ and Y¹ are selected such thatwhen X is O, then Y¹ and R³ cannot form ring B; each Q¹ is independentlyalkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, arylor heteroaryl; each Q¹ is optionally substituted with one to threegroups Q²; each Q² is independently alkyl, halo, haloalkyl, aryl orhaloaryl; each R^(a) is independently alkylene or a direct bond; R^(b)is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,aryl, heteroaryl or heterocyclyl; each R^(c) is independently hydrogenor alkyl; each R^(d) is independently alkyl, aryl, cycloalkyl,heteroaryl, heterocyclyl or —R^(a)OR^(b); each R^(d) is optionallysubstituted with one to three groups Q¹; R¹ and R² are selected asfollows: i) R¹ and R² are each independently hydrogen, alkyl orcycloalkyl; or ii) R¹ and R² together with the carbon atom on which theyare substituted form an optionally substituted saturated or unsaturatedring A, where the substituents on ring A, when present, are selectedfrom one to three groups Q¹; R⁴, R⁵, R⁶, R⁷ and R⁸ are eachindependently hydrogen or alkyl; R⁹ is aryl or heteroaryl, eachoptionally substituted with one to four substituents Q¹; R¹⁰ isalkylene; Z¹ and Z² are selected as follows: i) Z¹ is hydrogen or alkyl;and Z² is aryl, cycloalkyl, heteroaryl or heterocyclyl, each optionallysubstituted with one to four substituents Q³; or ii) Z¹ and Z² togetherwith the nitrogen atom on which they are substituted form an optionallysubstituted saturated or unsaturated ring C, where the substituents onring C, when present, are selected from one to three groups Q³; each Q³is independently selected from alkyl, halo, cyano, cycloalkyl,heterocyclyl, aryl, heteroaryl, —R¹¹OR¹², —R¹¹OR¹¹OR¹², —R¹¹N(R¹³)(R¹⁴),—R¹¹SR¹², —R¹¹OR¹¹N(R¹³)(R¹⁴), —R¹¹C(J)N(R¹³)(R¹⁴),—R¹¹OR¹¹C(J)N(R¹³)(R¹⁴), —C(J)R¹⁵ and R¹¹S(O)_(t)R¹⁶; where each Q³ isoptionally substituted with one to three groups Q⁴, where each Q⁴ isindependently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl;each R¹¹ is independently alkylene, alkenylene or a direct bond; eachR¹² is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; R¹³ and R¹⁴are selected as follows: i) R¹³ and R¹⁴ are each independently hydrogen,alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl,heteroaryl or heterocyclyl; or ii) R¹³ and R¹⁴ together with thenitrogen atom on which they are substituted form a 5 or 6-memberedheterocyclyl or heteroaryl ring, optionally substituted with one or twoalkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl; each R¹⁵ isindependently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl,heteroaryl, heterocyclyl or heterocyclyl; each R¹⁶ is independentlyhydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl,heteroaryl or heterocyclyl; J is O or S; and t is 0-2.
 2. The compoundof claim 1, wherein X and Y are selected as follows: i) X is C═O; and Yis —R^(a)OR^(b); or ii) X is —O—; Y is hydrogen, alkyl, aryl, arylalkyl,heteroarylalkyl or —C(O)R^(d); where the alkyl and aryl groups areoptionally substituted with one or two groups selected from alkyl andhalo; R³, Y¹, Y² and Y³ are selected as follows: i) Y¹ together with R³forms an optionally substituted saturated or unsaturated ring B, wheresubstituents on ring B, when present, are selected from one to threegroups Q³; Y² is absent, hydrogen or alkyl; and Y³ is absent, hydrogenor alkyl; or ii) R³ is hydrogen or alkyl; Y¹ and Y² together are ═O; andY³ is —N(Z¹)(Z²); X, Y, R³ and Y¹ are selected such that when X is O,then Y¹ and R³ cannot form ring B; R^(a) is alkylene or a direct bond;R^(b) is hydrogen, alkyl or aryl; R^(d) is aryl or aryloxy; R¹ and R²are selected as follows: i) R¹ and R² are each independently hydrogen oralkyl; or ii) R¹ and R² together with the carbon atom on which they aresubstituted form a cycloalkyl ring; R⁴, R⁵, R⁶, R⁷ and R⁸ are eachindependently hydrogen or alkyl; R⁹ is aryl or heteroaryl, eachoptionally substituted with one to four substituents selected from halo,alkyl and haloalkyl; R¹⁰ is alkylene; Z¹ is hydrogen or alkyl; Z² isaryl or heteroaryl, each optionally substituted with one to foursubstituents Q³; each Q³ is independently selected from alkyl,haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, —R¹¹OR¹², —C(O)R¹⁵and —C(O)NH₂; R¹¹ is alkylene or a direct bond; R¹² is hydrogen, alkylor haloalkyl; and R¹⁵ is hydroxyl or alkyl.
 3. The compound of claim 1,having formula II

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof.
 4. The compound of claim 3, wherein Xand Y are selected as follows: i) X is C═O; and Y is —R^(a)OR^(b); orii) X is —O—; Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or—C(O)R^(d); where the alkyl and aryl groups are optionally substitutedwith one or two groups selected from alkyl and halo; R^(a) is alkyleneor a direct bond; R^(b) is hydrogen, alkyl or aryl; R^(d) is aryl oraryloxy; R¹ and R² are selected as follows: i) R¹ and R² are eachindependently hydrogen or alkyl; or ii) R¹ and R² together with thecarbon atom on which they are substituted form a cycloalkyl ring; R³,R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently hydrogen or alkyl; R⁹ isaryl or heteroaryl, each optionally substituted with one to foursubstituents selected from halo, alkyl and haloalkyl; R¹⁰ is alkylene;Z¹¹ is hydrogen or alkyl; Z² is aryl or heteroaryl, each optionallysubstituted with one to four substituents Q³; each Q³ is independentlyselected from alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl,heteroaryl, —R¹¹OR¹², —C(O)R¹⁵ and —C(O)NH₂; each R¹¹ is independentlyalkylene or a direct bond; R¹² is hydrogen, alkyl or haloalkyl; and R¹⁵is hydroxyl or alkyl.
 5. The compound of claim 3, wherein R⁹ is phenylor pyrimidinyl, each optionally substituted with one to foursubstituents selected from halo, alkyl and haloalkyl.
 6. The compound ofclaim 1, having formula II

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein X and Y are selected asfollows: i) X is C═O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, —R^(a)OR^(b), or —R^(a)N(R^(c))(R^(d)); or ii) X is —O—, or—N(R^(c))—; Y is hydrogen, —C(O)R^(d), alkyl, cycloalkyl, heterocyclyl,aryl or heteroaryl; Y is optionally substituted with one to three groupsQ¹; each Q¹ is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy,cycloalkyl, heterocyclyl, aryl or heteroaryl; each Q¹ is optionallysubstituted with one to three groups Q²; each Q² is independently alkyl,halo, haloalkyl, aryl or haloaryl; each R^(a) is independently alkyleneor a direct bond; R^(b) is hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; each R^(c) isindependently hydrogen or alkyl; each R^(d) is independently alkyl,aryl, cycloalkyl, heteroaryl, heterocyclyl or —R^(a)OR^(b); each R^(d)is optionally substituted with one to three groups Q¹; R¹ and R² areselected as follows: i) R¹ and R² are each independently hydrogen, alkylor cycloalkyl; or ii) R¹ and R² together with the carbon atom on whichthey are substituted form an optionally substituted saturated orunsaturated ring A, where substituents on ring A, when present, areselected from one to three groups Q¹; R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are eachindependently hydrogen or alkyl; R¹⁰ is alkylene; each Q⁵ isindependently alkyl, halo or haloalkyl; Z¹ is hydrogen or alkyl; Z² isaryl, cycloalkyl, heteroaryl or heterocyclyl, each optionallysubstituted with one to four substituents Q³; each Q³ is independentlyselected from alkyl, halo, cyano, cycloalkyl, heterocyclyl, aryl,heteroaryl, —R¹¹OR¹², —R¹¹OR¹¹OR¹², —R¹¹N(R¹³)(R¹⁴), —R¹¹SR¹²,—R¹¹OR¹¹N(R¹³)(R¹⁴), —R¹¹C(J)N(R¹³)(R¹⁴), —R¹¹OR¹¹C(J)N(R¹³)(R¹⁴),—C(J)R¹⁵ and R¹¹S(O)_(t)R¹⁶; where each Q³ is optionally substitutedwith one to three groups Q⁴, where each Q⁴ is independently alkyl, halo,haloalkyl, hydroxyl, alkoxy or cycloalkyl; each R¹¹ is independentlyalkylene, alkenylene or a direct bond; each R¹² is independentlyhydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl,heteroaryl or heterocyclyl; R¹³ and R¹⁴ are selected as follows: i) R¹³and R¹⁴ are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; or ii) R¹³and R¹⁴ together with the nitrogen atom on which they are substitutedform a 5 or 6-membered heterocyclyl or heteroaryl ring, optionallysubstituted with one or two alkyl, halo, haloalkyl, hydroxyl, alkoxy orcycloalkyl; each R¹⁵ is independently hydroxy, alkyl, haloalkyl, alkoxy,cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclyl; each R¹⁶ isindependently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl; J is O or S; t is 0-2; andm is 0-4.
 7. The compound of claim 6, having formula V

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof.
 8. The compound of claim 7, wherein Xand Y are selected as follows: i) X is C═O; and Y is —R^(a)OR^(b); orii) X is —O—; Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or—C(O)R^(d); where the alkyl and aryl groups are optionally substitutedwith one or two groups selected from alkyl and halo; R^(a) is alkyleneor a direct bond; R^(b) is hydrogen, alkyl or aryl; R^(d) is aryl oraryloxy; R¹ and R² are selected as follows: i) R¹ and R² are eachindependently hydrogen or alkyl; or ii) R¹ and R² together with thecarbon atom on which they are substituted form a cycloalkyl ring; R³,R⁴, R⁵ and R⁶ are each independently hydrogen or alkyl; R¹⁰ is alkylene;Z¹ is hydrogen or alkyl; each Q³ is independently selected from alkyl,haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, —R¹¹OR¹², —C(O)R¹⁵and —C(O)NH₂; each R¹¹ is independently alkylene or a direct bond; R¹²is hydrogen, alkyl or haloalkyl; R¹⁵ is hydroxyl or alkyl; each Q⁵ isindependently alkyl, halo or haloalkyl; m is 0-4; and n is 0-2.
 9. Thecompound of claim 1, wherein X and Y are selected as follows: i) X isC═O; and Y is —R^(a)OR^(b); or ii) X is —O—; Y is hydrogen, alkyl, aryl,arylalkyl, heteroarylalkyl or —C(O)R^(d); where the alkyl and arylgroups are optionally substituted with one or two groups selected fromalkyl and halo; R^(a) is alkylene or a direct bond; R^(b) is hydrogen,alkyl or aryl; R^(d) is aryl or aryloxy; R¹ and R² are selected asfollows: i) R¹ and R² are each independently hydrogen or alkyl; or ii)R¹ and R² together with the carbon atom on which they are substitutedform a cycloalkyl ring; R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each independentlyhydrogen or alkyl; R⁹ is aryl or heteroaryl, each optionally substitutedwith one to four substituents selected from halo, alkyl and haloalkyl;R¹⁰ is alkylene; Z¹ is hydrogen or alkyl; each Q³ is independentlyselected from alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl,heteroaryl, —R¹¹OR¹², —C(O)R¹⁵ and —C(O)NH₂; R¹¹ is alkylene or a directbond; R¹² is hydrogen, alkyl or haloalkyl; R¹⁵ is hydroxyl or alkyl;each Q⁵ is independently alkyl, halo or haloalkyl; m is 0-4; and n is0-2.
 10. The compound of claim 1, having formula VIII

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein each Q⁶ is independently alkyl,halo or haloalkyl; and m is 0-4.
 11. The compound of claim 10, whereinR^(b) is hydrogen; R¹ and R² are selected as follows: i) R¹ and R² areeach independently hydrogen or alkyl; or ii) R¹ and R² together with thecarbon atom on which they are substituted form a 3-5 membered cycloalkylring; R³, R⁴, R⁵ and R⁶ are each independently hydrogen or alkyl; Z¹ ishydrogen or alkyl; Z² is aryl or heteroaryl, each optionally substitutedwith one to four substituents Q³; each Q³ is independently selected fromalkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, —R¹¹OR¹²,—C(O)R¹⁵ and —C(O)NH₂; R¹⁰ is —CH₂— or —CH₂—CH₂—; R¹¹ is alkylene or adirect bond; R¹² is hydrogen, alkyl or haloalkyl; R¹⁵ is hydroxyl oralkyl; Q⁶ is independently alkyl, halo or haloalkyl; and m is 0-4. 12.The compound of claim 1, wherein R¹⁰ is lower alkylene.
 13. The compoundof claim 12, wherein R¹⁰ is methylene or ethylene.
 14. The compound ofclaim 1, wherein i) R¹ and R² are each independently hydrogen or methyl;or ii) R¹ and R² together with the carbon atom on which they aresubstituted form a cyclopentyl ring.
 15. The compound of claim 1,wherein Z² is selected from phenyl, pyridinyl, pyrimidyl, naphthyl,indazolyl, quinolinyl, isoquinolynyl and benzoisothiazolyl; eachoptionally substituted with one or two Q³ groups, and each Q³ isindependently selected from halo, alkyl, haloalkyl, arylalkyl, alkoxy,alkylcarbonyl, haloalkoxy, cyano, aryl, heteroaryl and aminocarbonyl.16. The compound of claim 1, having formula XIV

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof; wherein X is C═O; Y is alkyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, —R^(a)OR^(b), or—R^(a)N(R^(c))(R^(d)); each optionally substituted with one to threegroups Q¹; each Q¹ is independently alkyl, halo, haloalkyl, hydroxyl,alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; each Q¹ isoptionally substituted with one to three groups Q²; each Q² isindependently alkyl, halo, haloalkyl, aryl or haloaryl; each R^(a) isindependently alkylene or a direct bond; R^(b) is hydrogen, alkyl,haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl; R^(c) is hydrogen or alkyl; R^(d) is alkyl, aryl,cycloalkyl, heteroaryl, heterocyclyl or —R^(a)OR^(b); each R^(d) isoptionally substituted with one to three groups Q¹; R¹ and R² areselected as follows: i) R¹ and R² are each independently hydrogen, alkylor cycloalkyl; or ii) R¹ and R² together with the carbon atom on whichthey are substituted form an optionally substituted saturated orunsaturated ring A, where the substituents on ring A, when present, areselected from one to three groups Q¹; R⁴, R⁵, R⁶, R⁷ and R⁸ are eachindependently hydrogen or alkyl; R⁹ is aryl or heteroaryl, eachoptionally substituted with one to four substituents Q¹; R¹⁰ isalkylene; each Q³ is independently selected from alkyl, halo, cyano,cycloalkyl, heterocyclyl, aryl, heteroaryl, —R¹¹OR¹², —R¹¹R¹¹OR¹²,—R¹¹N(R¹³)(R¹⁴), —R¹¹SR¹², —R¹¹OR¹¹N(R¹³)(R¹⁴), —R¹¹C(J)N(R¹³)(R¹⁴),—R¹¹OR¹¹C(J)N(R¹³)(R¹⁴), —C(J)R¹⁵ and R¹¹S(O)_(t)R¹⁶; where each Q³ isoptionally substituted with one to three groups Q⁴, where each Q⁴ isindependently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl;each R¹¹ is independently alkylene, alkenylene or a direct bond; eachR¹² is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; R¹³ and R¹⁴are selected as follows: i) R¹³ and R¹⁴ are each independently hydrogen,alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl,heteroaryl or heterocyclyl; or ii) R¹³ and R¹⁴ together with thenitrogen atom on which they are substituted form a 5 or 6-memberedheterocyclyl or heteroaryl ring, optionally substituted with one or twoalkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl; each R¹⁵ isindependently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl,heteroaryl, heterocyclyl or heterocyclyl; each R¹⁶ is independentlyhydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl,heteroaryl or heterocyclyl; J is O or S; t is 0-2; and n is 0-3.
 17. Thecompound of claim 16, wherein X is C═O; and Y is —R^(a)OR^(b); R^(a) isalkylene or a direct bond; R^(b) is hydrogen or alkyl; R¹ and R² areeach hydrogen; R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently hydrogen oralkyl; R⁹ is aryl or heteroaryl, each optionally substituted with one tofour halo; R¹⁰ is alkylene; each Q³ is halo; and n is 0-3.
 18. Thecompound of claim 1, having formula XVII

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein each Q³ is halo; n is 0-2; eachQ⁷ is halo, and x is 0-4.
 19. The compound of claim 17, wherein Q³ ischloro; n is 1; each Q⁷ is fluoro and x is
 4. 20. A pharmaceuticalcomposition, comprising the compound of claim 1 and a pharmaceuticallyacceptable carrier.
 21. A method of treating a disease comprisingadministering a therapeutically effective amount of the compound of anyone of claim 1, wherein the disease is selected from gastrointestinaldisease, respiratory disease, cardiovascular disease, dermatologicaldisease, rheumatological diseases, kidney disease, autoimmune disease,CNS disease, inflammatory disease, liver disease, cancer andophthalmological disease.